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Articles 31 - 60 of 183

Full-Text Articles in Molecular Biology

Kat-Independent Gene Regulation By Tip60 Promotes Esc Self-Renewal But Not Pluripotency, Diwash Acharya, Sarah J. Hainer, Yeonsoo Yoon, Feng Wang, Ingolf Bach, Jaime A. Rivera-Perez, Thomas G. Fazzio Apr 2017

Kat-Independent Gene Regulation By Tip60 Promotes Esc Self-Renewal But Not Pluripotency, Diwash Acharya, Sarah J. Hainer, Yeonsoo Yoon, Feng Wang, Ingolf Bach, Jaime A. Rivera-Perez, Thomas G. Fazzio

Pediatric Publications and Presentations

Although histone-modifying enzymes are generally assumed to function in a manner dependent on their enzymatic activities, this assumption remains untested for many factors. Here, we show that the Tip60 (Kat5) lysine acetyltransferase (KAT), which is essential for embryonic stem cell (ESC) self-renewal and pre-implantation development, performs these functions independently of its KAT activity. Unlike ESCs depleted of Tip60, KAT-deficient ESCs exhibited minimal alterations in gene expression, chromatin accessibility at Tip60 binding sites, and self-renewal, thus demonstrating a critical KAT-independent role of Tip60 in ESC maintenance. In contrast, KAT-deficient ESCs exhibited impaired differentiation into mesoderm and endoderm, demonstrating a KAT-dependent function ...


Antisense Oligonucleotides Used To Target The Dux4 Mrna As Therapeutic Approaches In Faciosscapulohumeral Muscular Dystrophy (Fshd), Eugenie Ansseau, Celine Vanderplanck, Armelle Wauters, Scott Q. Harper, Frederique Coppee, Alexandra Belayew Mar 2017

Antisense Oligonucleotides Used To Target The Dux4 Mrna As Therapeutic Approaches In Faciosscapulohumeral Muscular Dystrophy (Fshd), Eugenie Ansseau, Celine Vanderplanck, Armelle Wauters, Scott Q. Harper, Frederique Coppee, Alexandra Belayew

Wellstone Center for FSHD Publications

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally ...


A Microrna Family Exerts Maternal Control On Sex Determination In C. Elegans, Katherine Mcjunkin, Victor R. Ambros Feb 2017

A Microrna Family Exerts Maternal Control On Sex Determination In C. Elegans, Katherine Mcjunkin, Victor R. Ambros

Program in Molecular Medicine Publications and Presentations

Gene expression in early animal embryogenesis is in large part controlled post-transcriptionally. Maternally contributed microRNAs may therefore play important roles in early development. We elucidated a major biological role of the nematode mir-35 family of maternally contributed essential microRNAs. We show that this microRNA family regulates the sex determination pathway at multiple levels, acting both upstream of and downstream from her-1 to prevent aberrantly activated male developmental programs in hermaphrodite embryos. Both of the predicted target genes that act downstream from the mir-35 family in this process, suppressor-26 (sup-26) and NHL (NCL-1, HT2A, and LIN-41 repeat) domain-containing-2 (nhl-2), encode RNA-binding ...


Transcriptional And Post-Transcriptional Regulation Of Histone Variant H2a.Z During Sea Urchin Development, Mihai Hajdu Feb 2017

Transcriptional And Post-Transcriptional Regulation Of Histone Variant H2a.Z During Sea Urchin Development, Mihai Hajdu

All Dissertations, Theses, and Capstone Projects

Histone variant H2A.Z promotes chromatin accessibility at transcriptional regulatory elements and is developmentally regulated in metazoans. We characterize the transcriptional and post-transcriptional regulation of H2A.Z in the purple sea urchin Strongylocentrotus purpuratus. H2A.Z depletion by antisense translation-blocking morpholino oligonucleotides during early development causes developmental collapse, in agreement with its previously demonstrated general role in transcriptional multipotency. During H2A.Z peak expression in 24-h embryos, endogenous H2A.Z 3’ UTR sequences stabilize GFP mRNAs relative to those with SV40 3’ UTR sequences, although the 3’UTR of H2A.Z does not determine the spatial distribution of H2A.Z ...


Amplification Of Adipogenic Commitment By Vstm2a, Blandine Secco, Peter L. Lee, David A. Guertin, Mathieu Laplante Jan 2017

Amplification Of Adipogenic Commitment By Vstm2a, Blandine Secco, Peter L. Lee, David A. Guertin, Mathieu Laplante

UMass Metabolic Network Publications

Despite progress in our comprehension of the mechanisms regulating adipose tissue development, the nature of the factors that functionally characterize adipose precursors is still elusive. Defining the early steps regulating adipocyte development is needed for the generation of tools to control adipose tissue size and function. Here, we report the discovery of V-set and transmembrane domain containing 2A (VSTM2A) as a protein expressed and secreted by committed preadipocytes. VSTM2A expression is elevated in the early phases of adipogenesis in vitro and adipose tissue development in vivo. We show that VSTM2A-producing cells associate with the vasculature and express the common surface ...


Investigating The Essential Roles Of Dprl-1 In Drosophila Melanogaster, Alex Lee Jan 2017

Investigating The Essential Roles Of Dprl-1 In Drosophila Melanogaster, Alex Lee

Summer Research

Phosphatase of Regenerating Liver (PRL) proteins regulate a number of important cellular processes, including cell growth and division. Humans have three PRL proteins: PRL-1, PRL-2, and PRL-3. An accumulation of evidence has shown that elevated levels of PRLs are strongly correlated with uncontrollable growth and metastasis of tumors. However, contradictory findings have arisen indicating that PRLs instead function to halt cell division thereby preventing uncontrollable tumor growth. In light of these results, the underlying mechanisms regarding how PRLs function within cellular processes remains unclear. To investigate the functions of PRLs, we will create transgenic fruit flies (Drosophila melanogaster) with knockout ...


Elucidating The Ligand-Specific Role Of Tetraspanin12 As An Essential Co-Activator In Norrin/Frizzled4 Signaling And Retinal Vascularization, Maria B. Lai Jan 2017

Elucidating The Ligand-Specific Role Of Tetraspanin12 As An Essential Co-Activator In Norrin/Frizzled4 Signaling And Retinal Vascularization, Maria B. Lai

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Genetic evidence indicates that specific combinations of accessory proteins and ligands mediate vascular Frizzled (FZD) signaling via beta-catenin in different CNS structures. Accessory proteins in FZD receptor complexes are thought to determine ligand-selectivity and signaling amplitude. In the retina, TSPAN12 is an essential co-activator in Norrin/FZD4 signaling to mediate angiogenesis. The genes encoding mediators of Norrin/FZD4 signaling are linked to familial exudative vitreoretinopathy (FEVR), an inherited retinal disease that can lead to blindness. Yet, the molecular function of TSPAN12 and the specific cell type in which TSPAN12 functions in the retina remains poorly understood. Here, I utilized binding ...


Insights Into Retinal Cell Fate Determination In Vertebrates Using Transcriptomic Profiling And Genome Editing, Rebecca Chowdhury Jan 2017

Insights Into Retinal Cell Fate Determination In Vertebrates Using Transcriptomic Profiling And Genome Editing, Rebecca Chowdhury

Graduate Theses and Dissertations

Deciphering the mechanisms of development of retinal neurons is not only of immense interest to developmental biologists, but is also vital for regenerative therapeutic applications. To attain this goal, it is critical to understand how specific intrinsic factors control cell fate decisions and neuronal maturation processes. In the retina, Atoh7 is a highly conserved transcription factor that is essential for retinal ganglion cell development in the developing mouse and zebrafish. Atoh7 labels a subset of cells in the developing retina that are progressing from a progenitor to a differentiated state. To capture cells during the window when the cell fate ...


Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude, Ryan James Cedeno Jan 2017

Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude, Ryan James Cedeno

Publicly Accessible Penn Dissertations

Epigenetic factors guide chromatin remodeling during cell state transitions and confer resistance to genotoxic stressors that could induce deleterious transformations. A particularly peculiar component of the epigenome with emerging roles in fine-tuning cell identity and upholding genomic stability is the structural histone variant macroH2A. Relatively little is currently known about macroH2A’s influence on overall cell developmental potency and less still is known about macroH2A’s contributions to adult stem cell identity and function in vivo. In this work, we use induced pluripotent stem cell (iPSC) reprogramming and the murine intestinal stem cell (ISC) system to model macroH2A’s overall ...


Characterizing A Signaling Network That Maintains Hematopoietic Stem Cells, Michelle Nguyen-Mccarty Jan 2017

Characterizing A Signaling Network That Maintains Hematopoietic Stem Cells, Michelle Nguyen-Mccarty

Publicly Accessible Penn Dissertations

Hematopoietic stem cells (HSCs) are able to self-renew and to differentiate into all blood cells. HSCs reside in a low-perfusion niche and depend on local signals to survive and to maintain the capacity for self-renewal. HSCs removed from the niche can survive if they receive hematopoietic cytokines, but they then lose the ability to self-renew. However, we showed previously that simultaneous inhibition of glycogen synthase kinase-3 (GSK-3) and mammalian target of rapamycin complex 1 (mTORC1) maintains HSC function ex vivo without the need for exogenous cytokines. As these experiments were initially done in heterogeneous cell populations, I then showed that ...


Studies On The Molecular Underpinnings Of Sex Determination Mechanism Evolution And Molecular Sexing Tools In Turtles, Robert Alan Literman Jan 2017

Studies On The Molecular Underpinnings Of Sex Determination Mechanism Evolution And Molecular Sexing Tools In Turtles, Robert Alan Literman

Graduate Theses and Dissertations

Sex determination mechanisms (SDMs) direct the development of individuals towards a male or female fate, and in vertebrates they are typically controlled by an individual’s genotypic content (genotypic sex determination, GSD) or through an environmental cue experienced during development, mainly temperature (temperature-dependent sex determination, TSD). Among vertebrates, SDMs are surprisingly labile, transitioning between different forms of TSD and GSD in some lineages more than others. Turtles represent a model clade to study SDM evolution, as multiple independent transitions between TSD and GSD have occurred throughout their evolution and a growing number of genomic datasets have become available.

This dissertation ...


Ctcf-Mediated Topological Boundaries During Development Foster Appropriate Gene Regulation, Varun Narendra, Milica Bulajic, Job Dekker, Esteban O. Mazzoni, Danny Reinberg Dec 2016

Ctcf-Mediated Topological Boundaries During Development Foster Appropriate Gene Regulation, Varun Narendra, Milica Bulajic, Job Dekker, Esteban O. Mazzoni, Danny Reinberg

Program in Systems Biology Publications and Presentations

The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation. Moreover, our data suggest that CTCF-dependent boundary function can be modulated by competing forces, such as the self-assembly of polycomb domains ...


Rna Sequencing Analysis Of The Developing Chicken Retina, Christophe Langouet-Astrie*, Annamarie Meinsen*, Emily R. Grunwald*, Stephen Turner, Raymond A. Enke Nov 2016

Rna Sequencing Analysis Of The Developing Chicken Retina, Christophe Langouet-Astrie*, Annamarie Meinsen*, Emily R. Grunwald*, Stephen Turner, Raymond A. Enke

Ray Enke Ph.D.

RNA sequencing transcriptome analysis using massively parallel next generation sequencing technology provides the capability to understand global changes in gene expression throughout a range of tissue samples. Development of the vertebrate retina requires complex temporal orchestration of transcriptional activation and repression. The chicken embryo (Gallus gallus) is a classic model system for studying developmental biology and retinogenesis. Existing retinal transcriptome projects have been critical to the vision research community for studying aspects of murine and human retinogenesis, however, there are currently no publicly available data sets describing the developing chicken retinal transcriptome. Here we used Illumina RNA sequencing (RNA-seq) analysis ...


Dna Methylation Directs Genomic Localization Of Mbd2 And Mbd3 In Embryonic Stem Cells, Sarah J. Hainer, Kurtis N. Mccannell, Jun Yu, Ly-Sha Ee, Lihua (Julie) Zhu, Oliver J. Rando, Thomas G. Fazzio Nov 2016

Dna Methylation Directs Genomic Localization Of Mbd2 And Mbd3 In Embryonic Stem Cells, Sarah J. Hainer, Kurtis N. Mccannell, Jun Yu, Ly-Sha Ee, Lihua (Julie) Zhu, Oliver J. Rando, Thomas G. Fazzio

Open Access Articles

Cytosine methylation is an epigenetic and regulatory mark that functions in part through recruitment of chromatin remodeling complexes containing methyl-CpG binding domain (MBD) proteins. Two MBD proteins, Mbd2 and Mbd3, were previously shown to bind methylated or hydroxymethylated DNA, respectively; however, both of these findings have been disputed. Here, we investigated this controversy using experimental approaches and re-analysis of published data and find no evidence for methylation-independent functions of Mbd2 or Mbd3. We show that chromatin localization of Mbd2 and Mbd3 is highly overlapping and, unexpectedly, we find Mbd2 and Mbd3 are interdependent for chromatin association. Further investigation reveals that ...


Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang Nov 2016

Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang

University of Massachusetts Medical School Faculty Publications

Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules. Electron microscopy revealed increased cytoplasmic vesicles, fiber-like structures, abnormal accumulation of mitochondria and a decrease in mature lysosomes. The few developed sperm had ...


Regulation Of X-Linked Gene Expression During Early Mouse Development By Rlim, Feng Wang, Jongdae Shin, Jeremy Shea, Jun Yu, Ana Boskovic, Meg Byron, Xiaochun Zhu, Alex K. Shalek, Aviv Regev, Jeanne B. Lawrence, Eduardo M. Torres, Lihua J. Zhu, Oliver J. Rando, Ingolf Bach Sep 2016

Regulation Of X-Linked Gene Expression During Early Mouse Development By Rlim, Feng Wang, Jongdae Shin, Jeremy Shea, Jun Yu, Ana Boskovic, Meg Byron, Xiaochun Zhu, Alex K. Shalek, Aviv Regev, Jeanne B. Lawrence, Eduardo M. Torres, Lihua J. Zhu, Oliver J. Rando, Ingolf Bach

Open Access Articles

Mammalian X-linked gene expression is highly regulated as female cells contain two and male one X chromosome (X). To adjust the X gene dosage between genders, female mouse preimplantation embryos undergo an imprinted form of X chromosome inactivation (iXCI) that requires both Rlim (also known as Rnf12) and the long non-coding RNA Xist. Moreover, it is thought that gene expression from the single active X is upregulated to correct for bi-allelic autosomal (A) gene expression. We have combined mouse genetics with RNA-seq on single mouse embryos to investigate functions of Rlim on the temporal regulation of iXCI and Xist. Our ...


Improved B Cell Development In Humanized Nod-Scid Il2rgammanull Mice Transgenically Expressing Human Stem Cell Factor, Granulocyte-Macrophage Colony-Stimulating Factor And Interleukin-3, Sonal Jangalwe, Leonard D. Shultz, Anuja Mathew, Michael A. Brehm Aug 2016

Improved B Cell Development In Humanized Nod-Scid Il2rgammanull Mice Transgenically Expressing Human Stem Cell Factor, Granulocyte-Macrophage Colony-Stimulating Factor And Interleukin-3, Sonal Jangalwe, Leonard D. Shultz, Anuja Mathew, Michael A. Brehm

Open Access Articles

INTRODUCTION: Immunodeficient mice engrafted with human immune systems support studies of human hematopoiesis and the immune response to human-specific pathogens. A significant limitation of these humanized mouse models is, however, a severely restricted ability of human B cells to undergo class switching and produce antigen-specific IgG after infection or immunization.

METHODS: In this study, we have characterized the development and function of human B cells in NOD-scid IL2Rgammanull (NSG) mice transgenically expressing human stem cell factor (SCF), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-3 (NSG-SGM3) following engraftment with human hematopoietic stem cells, autologous fetal liver, and thymic tissues (bone marrow ...


Autophagy-Independent Function Of Atg1 For Apoptosis-Induced Compensatory Proliferation, Mingli Li, Jillian L. Lindblad, Ernesto Perez, Andreas Bergmann, Yun Fan Aug 2016

Autophagy-Independent Function Of Atg1 For Apoptosis-Induced Compensatory Proliferation, Mingli Li, Jillian L. Lindblad, Ernesto Perez, Andreas Bergmann, Yun Fan

Molecular, Cell and Cancer Biology Publications

BACKGROUND: ATG1 belongs to the Uncoordinated-51-like kinase protein family. Members of this family are best characterized for roles in macroautophagy and neuronal development. Apoptosis-induced proliferation (AiP) is a caspase-directed and JNK-dependent process which is involved in tissue repair and regeneration after massive stress-induced apoptotic cell loss. Under certain conditions, AiP can cause tissue overgrowth with implications for cancer.

RESULTS: Here, we show that Atg1 in Drosophila (dAtg1) has a previously unrecognized function for both regenerative and overgrowth-promoting AiP in eye and wing imaginal discs. dAtg1 acts genetically downstream of and is transcriptionally induced by JNK activity, and it is required ...


Functions Of Argonaute Proteins In Self Versus Non-Self Recognition In The C. Elegans Germline: A Dissertation, Meetu Seth Aug 2016

Functions Of Argonaute Proteins In Self Versus Non-Self Recognition In The C. Elegans Germline: A Dissertation, Meetu Seth

GSBS Dissertations and Theses

Organisms employ sophisticated mechanisms to silence foreign nucleic acid, such as viruses and transposons. Evidence exists for pathways that sense copy number, unpaired DNA, or aberrant RNA (e.g., dsRNA), but the mechanisms that distinguish “self” from “non-self” are not well understood. Our studies on transgene silencing in C. elegans have uncovered an RNA surveillance system in which the PIWI protein, PRG-1, uses a vast repertoire of piRNAs to recognize foreign transcripts and to initiate epigenetic silencing. Partial base pairing by piRNAs is sufficient to guide PRG-1 targeting. PRG-1 in turn recruits RdRP to synthesize perfectly matching antisense siRNAs (22G-RNAs ...


Modeling And Analysis Of Germ Layer Formations Using Finite Dynamical Systems, Alexander Garza, Megan Eberle, Eric A. Eager Aug 2016

Modeling And Analysis Of Germ Layer Formations Using Finite Dynamical Systems, Alexander Garza, Megan Eberle, Eric A. Eager

Spora: A Journal of Biomathematics

The development of an embryo from a fertilised egg to a multicellular organism proceeds through numerous steps, with the formation of the three germ layers (endoderm, mesoderm, ectoderm) being one of the first. In this paper we study the mesendoderm (the tissue that collectively gives rise to both mesoderm and endoderm) gene regulatory network for two species, \textit{Xenopus laevis} and the axolotl (\textit{Ambystoma mexicanum}) using Boolean networks. We find that previously-established bistability found in these networks can be reproduced using this Boolean framework, provided that some assumptions used in previously-published differential equations models are relaxed. We conclude by ...


Suppression Of Ischemia In Arterial Occlusive Disease By Jnk-Promoted Native Collateral Artery Development, Kasmir Ramo, Koichi Sugamura, Siobhan M. Craige, John F. Keaney Jr., Roger J. Davis Aug 2016

Suppression Of Ischemia In Arterial Occlusive Disease By Jnk-Promoted Native Collateral Artery Development, Kasmir Ramo, Koichi Sugamura, Siobhan M. Craige, John F. Keaney Jr., Roger J. Davis

Davis Lab Publications

Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive ...


Morpholino-Mediated Knockdown Of Dux4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics, Jennifer C. J. Chen, Oliver D. King, Yuanfan Zhang, Nicholas P. Clayton, Carrie Spencer, Bruce M. Wentworth, Charles P. Emerson Jr., Kathryn R. Wagner Aug 2016

Morpholino-Mediated Knockdown Of Dux4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics, Jennifer C. J. Chen, Oliver D. King, Yuanfan Zhang, Nicholas P. Clayton, Carrie Spencer, Bruce M. Wentworth, Charles P. Emerson Jr., Kathryn R. Wagner

Cell and Developmental Biology Publications

Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These ...


Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez Aug 2016

Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez

UT GSBS Dissertations and Theses (Open Access)

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found ...


Promoter-Enhancer Looping At The Pparγ2 Locus During Adipogenic Differentiation Requires The Prmt5 Methyltransferase, Scott E. Leblanc, Qiong Wu, Pallavi Lamba, Said Sif, Anthony N. Imbalzano Jun 2016

Promoter-Enhancer Looping At The Pparγ2 Locus During Adipogenic Differentiation Requires The Prmt5 Methyltransferase, Scott E. Leblanc, Qiong Wu, Pallavi Lamba, Said Sif, Anthony N. Imbalzano

Imbalzano Lab Publications

PPARγ2 is a critical lineage-determining transcription factor that is essential for adipogenic differentiation. Here we report characterization of the three-dimensional structure of the PPARγ2 locus after the onset of adipogenic differentiation and the mechanisms by which it forms. We identified a differentiation-dependent loop between the PPARγ2 promoter and an enhancer sequence 10 kb upstream that forms at the onset of PPARγ2 expression. The arginine methyltransferase Prmt5 was required for loop formation, and overexpression of Prmt5 resulted in premature loop formation and earlier onset of PPARγ2 expression. Kinetic studies of regulatory factor interactions at the PPARγ2 promoter and enhancer revealed enhanced ...


The Role Of Daf-19 In Non-Ciliated Neurons: How Is Neural Development Regulated By Different Daf-19 Isoforms?, Zabdiel Ek Vazquez Jun 2016

The Role Of Daf-19 In Non-Ciliated Neurons: How Is Neural Development Regulated By Different Daf-19 Isoforms?, Zabdiel Ek Vazquez

Lawrence University Honors Projects

A degenerative disease-like phenotype, specifically reduction in synaptic protein levels in adult worms, is correlated with loss-of-function of the only RFX transcription factor gene, daf-19, in C. elegans. This gene encodes four known transcription factor isoforms, two of which are correlated with particular functions. The DAF-19C isoform activates genes responsible for cilia development, while DAF-19M is needed for cilia specification in males. A comparison of the transcriptome of daf-19 null and isogenic wild type adult worms suggests both positive and negative regulation of gene expression is correlated with the presence of DAF-19 proteins. We have assessed DAF-19 regulation of gene ...


The Unconventional Myosin Crinkled And Its Mammalian Orthologue Myo7a Regulate Caspases In Their Signalling Roles, Mariam H. Orme, Meghana Tare, Andreas Bergmann, Pascal Meier Mar 2016

The Unconventional Myosin Crinkled And Its Mammalian Orthologue Myo7a Regulate Caspases In Their Signalling Roles, Mariam H. Orme, Meghana Tare, Andreas Bergmann, Pascal Meier

Molecular, Cell and Cancer Biology Publications

Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-beta to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation ...


Staufen Negatively Modulates Microrna Activity In Caenorhabditis Elegans, Zhiji Ren, Isana Veksler-Lublinsky, David Morrissey, Victor Ambros Mar 2016

Staufen Negatively Modulates Microrna Activity In Caenorhabditis Elegans, Zhiji Ren, Isana Veksler-Lublinsky, David Morrissey, Victor Ambros

Victor R. Ambros

The double-stranded RNA-binding protein Staufen has been implicated in various post-transcriptional gene regulatory processes. Here we demonstrate that the Caenorhabditis elegans homolog of Staufen, STAU-1, functionally interacts with microRNAs. Loss-of-function mutations of stau-1 significantly suppress phenotypes of let-7 family microRNA mutants, a hypomorphic allele of dicer and a lsy-6 microRNA partial loss-of-function mutant. Furthermore, STAU-1 modulates the activity of lin-14, a target of lin-4 and let-7 family microRNAs, and this modulation is abolished when the 3' untranslated region of lin-14 is removed. Deep sequencing of small RNA cDNA libraries reveals no dramatic change in the levels of microRNAs, or other ...


Transgenic Drosophila For Investigating Dux4 And Frg1, Two Genes Associated With Facioscapulohumeral Muscular Dystrophy (Fshd), Takako I. Jones, Megan Parilla, Peter L. Jones Mar 2016

Transgenic Drosophila For Investigating Dux4 And Frg1, Two Genes Associated With Facioscapulohumeral Muscular Dystrophy (Fshd), Takako I. Jones, Megan Parilla, Peter L. Jones

Peter Jones Lab Publications

Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl ...


Staufen Negatively Modulates Microrna Activity In Caenorhabditis Elegans, Zhiji Ren, Isana Veksler-Lublinsky, David Morrissey, Victor R. Ambros Feb 2016

Staufen Negatively Modulates Microrna Activity In Caenorhabditis Elegans, Zhiji Ren, Isana Veksler-Lublinsky, David Morrissey, Victor R. Ambros

Program in Molecular Medicine Publications and Presentations

The double-stranded RNA-binding protein Staufen has been implicated in various post-transcriptional gene regulatory processes. Here we demonstrate that the Caenorhabditis elegans homolog of Staufen, STAU-1, functionally interacts with microRNAs. Loss-of-function mutations of stau-1 significantly suppress phenotypes of let-7 family microRNA mutants, a hypomorphic allele of dicer and a lsy-6 microRNA partial loss-of-function mutant. Furthermore, STAU-1 modulates the activity of lin-14, a target of lin-4 and let-7 family microRNAs, and this modulation is abolished when the 3' untranslated region of lin-14 is removed. Deep sequencing of small RNA cDNA libraries reveals no dramatic change in the levels of microRNAs, or other ...


Tenomodulin Promotes Human Adipocyte Differentiation And Beneficial Visceral Adipose Tissue Expansion, Ozlem Senol-Cosar, Rachel J. Roth Flach, Marina Distefano, Anil K. Chawla, Sarah M. Nicoloro, Juerg R. Straubhaar, Olga T. Hardy, Hye Lim Noh, Jason K. Kim, Martin Wabitsch, Philipp E. Scherer, Michael P. Czech Feb 2016

Tenomodulin Promotes Human Adipocyte Differentiation And Beneficial Visceral Adipose Tissue Expansion, Ozlem Senol-Cosar, Rachel J. Roth Flach, Marina Distefano, Anil K. Chawla, Sarah M. Nicoloro, Juerg R. Straubhaar, Olga T. Hardy, Hye Lim Noh, Jason K. Kim, Martin Wabitsch, Philipp E. Scherer, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal white adipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greater proliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice ...