Medicine and Health Sciences Commons^™

Pharmacogenetics: Cyps, Nat2 And 5-Htt Related To Antidepressants, Molly Kulp, Armond Cosiano, Kevin Krivanek, Amanda Lanker, Taylor Roberson, David F. Kisor

Pharmacy and Wellness Review

Pharmacogenetics (PGt), the study of a gene's influence on patient response to a drug, shows strong potential for explaining issues with efficacy related to antidepressant medications. Each year, antidepressants are one of the most commonly prescribed medications due to the millions of Americans affected by depression. Importantly, it is recognized that there is wide interpatient variability in drug response to antidepressants caused by genetic mutations, which can alter the pharmacodynamic (PD) and pharmacokinetic (PK) properties of various drugs used to treat depression. Proteins that are mainly involved in how patients respond to medications include receptors, drug-targeted proteins, drug transport proteins …

Phenoconversion: Drug-Drug-Gene Interactions, Molly Kulp, Emily Limberg, Brooke Marlowe, Taylor Roberson, David F. Kisor

Pharmacy and Wellness Review

Based on the extensive, poor, intermediate and ultrarapid phenotypes of patients, inferences may be made relative to drug metabolism, ultimately leading to changes in therapeutic drug choice or dosing. Phenoconversion is a phenomenon that occurs when an individual's drug metabolizing capacity is altered due to the combination of a drug-drug interaction and a drug-gene interaction. Phenoconversion can affect pharmacokinetics as well as pharmacodynamics. Some examples of phenoconversions include amiodarone-warfarin, duloxetine-codeine, rifampin-clopidogrel, and rifampinwarfarin. Pharmacists must consider phenoconversion in cases of multi-drug therapy.

Overview Of Kalydeco® (Ivacaftor) For Treatment Of Cystic Fibrosis, Andrew Skouby, Kayti Kintner, Kimberly Loughlin, Emily Blum, Michael Rush

Pharmacy and Wellness Review

Cystic fibrosis (CF) is a genetic disease associated with specific gene mutations that presents with pulmonary inflammation and frequent lung infections, exocrine pancreatic insufficiency, altered sweat composition and declining lung function. Ivacaftor (Kalydeco®) was approved for treatment of cystic fibrosis in patients 6 years of age and older with a G551D mutation on the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a CFTR potentiator and does not work in patients with a mutation of the F508del. Efficacy has been demonstrated in several trials with a primary outcome of improved FEV1, improvements in pulmonary exacerbations, patient-reported decrease in respiratory …

Ado-Trastuzumab Emtansine For Her2 Positive Breast Cancer, Kimberly Baucher, Taylor Beale, Maria Laikos, Eric Stack, Mary Ellen Hethcox

Pharmacy and Wellness Review

No abstract provided.

Use Of Pharmacogenomics In Mtm Services, Molly Kulp, Halle Orlinski, Zachary R. Jones, Zachary Crawford, David Kisor

Pharmacy and Wellness Review

Incorporation of pharmacogenomic data into Medication Therapy Management (MTM) allows pharmacists to optimize treatment regimens for patients leading to better overall outcomes. Utilizing pharmacogenomics makes it easier for health care professionals to initiate medication regimens with reduced adverse reactions, improves outcomes due to specialized dosing and therapies and allows the treatment process to be as cost-effective as possible for the patient. Pharmacists have an opportunity to educate the rest of the health care team on issues such as: which ethnicities possess higher odds of carrying certain genetic variants, the most common or most relevant medications that can have variable effects …

The Impact Of Pharmacogenomics On Chemotherapeutic Drug Development And Use, Lara Long, Amy Pasternak, Ellen Hazelet, David Kisor

Pharmacy and Wellness Review

Cancer therapy is largely dependent on general treatment guidelines, and patients undergoing chemotherapy often experience treatment failure with standard drugs. The development of individualized drug therapy through pharmacogenomics has the potential to enhance chemotherapy regimen selection and improve patient outcomes. Antineoplastic agents such as cetuximab and trastuzumab are effective in treating cancers possessing specific genetic biomarker characteristics. Patients need to undergo genetic testing before these agents are administered to ensure appropriate use. Cetuximab has been shown to improve outcomes in metastatic colorectal cancers and head and neck squamous cell carcinomas positive for EGFR. Trastuzumab has shown benefit in human epidermal …

The Pharmacogenetics Of Opioid Pain Management, Maryanne Ventura, Lauren Desko, Kimberly Gathers, Ashley Overy, David Kisor

Pharmacy and Wellness Review

High rates of interpatient variability in drug metabolism and drug response for nearly all medications lead to the hypothesis that assessment of an individual patient's genotype with respect to their ability metabolize certain drugs can be a useful tool in predicting a patient's responsiveness to certain medications. Evaluating patients using pharmacogenomics as a basis for assessment could allow pharmacists to decide which treatment options would be most efficacious in a given patient and, thereby, have significant impact in the clinical setting. This holds true especially in the case of prodrugs, which require in vivo activation to an active or more …

Preparing For The Genomic Age: Thiopurine S-Methytransferase Polymorphism, Hilary Stewart, Lisa Berni, Tyler Bulcher, Joel Rittenhouse, Ryan W. Naseman

Pharmacy and Wellness Review

Interpatient variability among medication doses has been a long-standing obstacle for many prescribers. Some medications result in increased morbidity and mortality in a small percentage of the population. For many years, the cause of such toxicities was unknown. This mystery has been resolved by the discovery that the abscence or abnormality of specific genes that code for receptros, drug-treated proteins, drug transport mechanisms, and drug metabolizing enzymes could alter how an affected individual will respond to a given drug. One such incidence is the genetic polymorphism in thiopurine s-methytransferase (TPMT). In comprehending the mechanism of this polymorphism, it is important …

Eugenics In The 21st Century, Jessica Linn Chin

Dissertations, Theses, and Capstone Projects

Eugenics is the science of enhancing the human population through the management of breeding and hereditary traits. This thesis explores the history of eugenics and shows how eugenic practices continue in the 21^st century with advancements in technology and positive eugenic goals that can result in adverse effects on the human body and society. When Sir Francis Galton coined the term eugenics in 1883, he intended to improve British society with the use of positive eugenics. Galton used positive eugenics to encourage people with good mental and physical qualities to produce more children. He avoided negative eugenics, which involved …

Screening And Diagnosing Spinal Muscular Atrophy By Use Of Buccal Swabs: A Validation Study Using Ddpcr, Anna Mackay

Honors Scholar Theses

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder characterized by progressive muscle weakness due to the degeneration of motor neurons. SMA is caused by a homozygous deletion, mutation or rearrangement in the Survival Motor Neuron 1 (SMN1) gene. Survival Motor Neuron 2 (SMN2) is located tandem to SMN1 and is identical to SMN1 except for a single nucleotide substitution in exon 7. SMA diagnosis and carrier status can be determined by droplet digital PCR (ddPCR). This study sought to validate Bio-Rad’s ddPCR SMN1and SMN2 gene determination copy number assay for SMA diagnosis and screening using buccal swabs specimens. Buccal …

Predicting Premature Birth Risk With Cfrna, Jason Lin, Jonathan Marin, John Santerre

SMU Data Science Review

Identifying which genes are early indicators for preterm births using cell-free ribonucleic acid (cfRNA) from non-invasive blood tests provided by pregnant women can improve prenatal care. Currently, there are no medical tests for early detection of preterm birth risk in routine checkups for pregnant women. Recent studies have shown potential genes that can predict preterm birth. Machine learning techniques are utilized to see if the Area Under the Curve (AUC) can be improved upon when evaluating the prediction accuracy for chosen genes sequences and concentrations. Using cell-free RNA data from non-invasive blood tests in conjunction with machine learning, we improve …

Rheumatoid Arthritis-Relevant Dna Methylation Changes Identified In Acpa-Positive Asymptomatic Individuals Using Methylome Capture Sequencing., Xiaojian Shao, Marie Hudson, Ines Colmegna, Celia M T Greenwood, Marvin J. Fritzler, Philip Awadalla, T Pastinen, Sasha Bernatsky

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk.

METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. …

New Insights Into Dna Methylation Signatures: Smarca2 Variants In Nicolaides-Baraitser Syndrome., Eric Chater-Diehl, Resham Ejaz, Cheryl Cytrynbaum, Michelle T. Siu, Andrei Turinsky, Sanaa Choufani, Sarah J. Goodman, Omar Abdul-Rahman, Melanie Bedford, Naghmeh Dorrani, Kendra Engleman, Josue Flores-Daboub, David Genevieve, Roberto Mendoza-Londono, Wendy Meschino, Laurence Perrin, Nicole Safina, Sharron Townshend, Stephen W. Scherer, Evdokia Anagnostou, Amelie Piton, Matthew Deardorff, Michael Brudno, David Chitayat, Rosanna Weksberg

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures.

METHODS: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification …

Integrative Analysis Of Vascular Endothelial Cell Genomic Features Identifies Aida As A Coronary Artery Disease Candidate Gene., Simon Lalonde, Valérie-Anne Codina-Fauteux, Sébastian Méric De Bellefon, Francis Leblanc, Mélissa Beaudoin, Marie-Michelle Simon, Rola Dali, Tony Kwan, Ken Sin Lo, T Pastinen, Guillaume Lettre

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene …

Updated Genes, Lifestyles, And Their Interactions For Human Longevity, Brenda Bin Su, Alexis Villafranca, Chunxiang Mao, Stephanie Hernandez, Stephanie Lozano, Masoud M. Zarei, Kesheng Wang, Saraswathy Nair, Chun Xu

Health & Biomedical Sciences Faculty Publications

Healthy aging is the prolonging of optimal wellbeing during the progressive decline in physiological functions that are necessary for survival. Two important components of aging include an individual’s genetic makeup and lifestyle choices such as diet and exercise. Genetic factors are responsible for the functional physiology of the body including cell maintenance, metabolism and apoptosis. The individual effects of genes and lifestyle choices on aging are reported mainly in Caucasian populations, with very limited studies in minority populations. In this review, we included the effects of genes and environment and the interaction between them on aging in Hispanic population in …

Microrna-374a, -4680, And -133b Suppress Cell Proliferation Through The Regulation Of Genes Associated With Human Cleft Palate In Cultured Human Palate Cells, Akiko Suzuki, Aimin Li, Mona Gajera, Nada Abdallah, Musi Zhang, Zhongming Zhao, Junichi Iwata

Faculty, Staff and Student Publications

BACKGROUND: Cleft palate (CP) is the second most common congenital birth defect; however, the relationship between CP-associated genes and epigenetic regulation remains largely unknown. In this study, we investigated the contribution of microRNAs (miRNAs) to cell proliferation and regulation of genes involved in CP development.

METHODS: In order to identify all genes for which mutations or association/linkage have been found in individuals with CP, we conducted a systematic literature search, followed by bioinformatics analyses for these genes. We validated the bioinformatics results experimentally by conducting cell proliferation assays and miRNA-gene regulatory analyses in cultured human palatal mesenchymal cells treated with …

Autoimmune Polyglandular Syndrome Type 1: A Case Report And Brief Review., Ifeanyi Nwosu, Oreoluwa Oladiran, Chinyere Ogbonna-Nwosu, Anulika Anyata

Reading Hospital Internal Medicine Residency

Autoimmune polyglandular syndrome (APS) type 1 is a rare autoimmune disorder inherited in an autosomal recessive pattern due to loss of function of the AIRE gene and defective removal of self-reactive T-lymphocytes during the process of thymic T cell maturation. Its manifestation starts early in life with the cardinal clinical disorders being one of muco-cutaneous candidiasis, Addison's disease, and hypoparathyroidism. Recognizing the syndromic nature of one autoimmune disease will facilitate an active search for other conditions which would allow early detection, management, follow-up, and most importantly patient education and counselling to avoid potential complications. We present the case of a …

Cyclin C Regulated Oxidative Stress Responsive Transcriptome In Mus Musculus Embryonic Fibroblasts, David C Stieg, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively …

Leptin Produced By Obesity-Altered Adipose Stem Cells Promotes Metastasis But Not Tumorigenesis Of Triple-Negative Breast Cancer In Orthotopic Xenograft And Patient-Derived Xenograft Models, Rachel A. Sabol, Annie C. Bowles, Alex Côté, Rachel Wise, Benjamen O'Donnell, Margarite D. Matossian, Fokhrul M. Hossain, Hope E. Burks, Luis Del Valle, Lucio Miele, Bridgette M. Collins-Burow, Matthew E. Burow, Bruce A. Bunnell

School of Medicine Faculty Publications

BACKGROUND: Breast cancer is the second leading cause of cancer deaths in the USA. Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with high rates of metastasis, tumor recurrence, and resistance to therapeutics. Obesity, defined by a high body mass index (BMI), is an established risk factor for breast cancer. Women with a high BMI have increased incidence and mortality of breast cancer; however, the mechanisms(s) by which obesity promotes tumor progression are not well understood. METHODS: In this study, obesity-altered adipose stem cells (obASCs) were used to evaluate obesity-mediated effects of TNBC. Both in vitro …

Gnrh Agonist Improves Hyperandrogenism In An Adolescent Girl With An Insulin Receptor Gene Mutation., Emily Paprocki, Romina Barral, Heidi Vanden Brink, Marla Lujan, Tania S. Burgert

Manuscripts, Articles, Book Chapters and Other Papers

Type A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range/dL), free testosterone 2.21 ng/dL (reference rangeA(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy …

Viral Whole Genome Sequencing For Antiviral Resistance In A Child With Dock8 Deficiency And Recurrent Hsv-1, Sean Stout, A. L. Greninger, Rangaraj Selvarangan, A. F. Freeman, Brandon D. Newell, Erin Stahl, Dwight Yin

Posters

We present the case of a child with dedicator of cytokinesis 8 (DOCK8) deficiency and chronic, resistant HSV-1 mucocutaneous infections to illustrate the clinical utility of viral whole genome sequencing to detect active and latent HSV resistance mutations.

Differential Iron Regulatory Genetics In 2d & 3d Culture Of Breast Cancer Cells, Tyler Hanna, Suzy Torti Ph. D, Frank Torti M.D., Mph, Nicole Farra Ph. D.

Honors Scholar Theses

The iron regulatory axis has consistently been shown to be perturbed in cancer cell lines relative to non-cancerous cell lines. As cancer cells rapidly divide and grow, they require iron to fuel many intracellular processes, including DNA replication and protein synthesis. Three-dimensional cell culture is an increasingly popular method of culture that purportedly more accurately mimics the in vivo microenvironment of cancers over traditional two-dimensional culture. This project was prompted by previous lab results to investigate differential iron regulatory gene expression in 2D and 3D spheroid culture models. We replicated the findings that the gene hepcidin is induced in 3D …

Exploring The Potential Yield Of Prenatal Testing By Evaluating A Postnatal Population With Structural Abnormalities, Peyton Busby

Dissertations and Theses (Open Access)

After identification of one or more structural abnormalities in a fetus, pregnant women are offered a host of different testing options to identify a possible genetic cause for the structural abnormality(ies). When considering what type of test to undertake, there is limited information on the diagnostic yield of the varying testing options. Some women may miss an opportunity to gain the information they are seeking or make a less informed decision when they choose a testing option after identification of a structural abnormality due to this lack of information. This study aimed to identify the potential diagnostic yield of all …

Neuroblastoma In Adolescents And Children Older Than 10 Years: Unusual Clinicopathologic And Biologic Features, Laura Mccarthy, Katherine Chastain, Terrie Flatt, Eugenio Taboada, Robert E. Garola, John Herriges, Linda D. Cooley, Atif Ahmed

Posters

This poster describes four cases of neuroblastoma diagnosed since 2008 in children greater than 10 years and presents their clinical, histologic and biologic features, emphasizing unusual clinicopathologic characteristics and the role of DNA microarray analysis and Next Generation Sequencing in their management.

The Impacts Of Insurance And Billing Considerations On The Practice And Attitudes Of Genetic Counselors, Emily Krosschell

Dissertations and Theses (Open Access)

Genesurance counseling has been identified as an integral part of many genetic counseling sessions, but little is known about the workflow impacts and genetic counselor perceptions of genesurance-related tasks. In this study, we aimed to characterize how insurance and billing considerations for genetic testing are being incorporated into genetic counselors’ practice; as well as describe current attitudes and challenges associated with their integration. An electronic survey was sent by email to members of the National Society of Genetic Counselors (NSGC). A total of 325 genetic counselors that provided direct patient care were included in data analysis. Results showed that the …

Ucp1 Expression-Associated Gene Signatures Of Human Epicardial Adipose Tissue., Kanta Chechi, Jinchu Vijay, Pierre Voisine, Patrick Mathieu, Yohan Bossé, Andre Tchernof, Elin Grundberg, Denis Richard

Manuscripts, Articles, Book Chapters and Other Papers

Multiple reports of uncoupling protein 1 (UCP1) expression have established its presence in human epicardial adipose tissue (eAT). Its functional relevance to eAT, however, remains largely unknown. In a recent study, we reported that adrenergic stimulation of eAT was associated with downregulation of secreted proteins involved in oxidative stress-related and immune-related pathways. Here, we explored the UCP1-associated features of human eAT using next-generation deep sequencing. Paired biopsies of eAT, mediastinal adipose tissue (mAT), and subcutaneous adipose tissue (sAT) obtained from cardiac surgery patients, with specific criteria of high and low expression of UCP1 in eAT, were subjected to RNA sequencing. …

Exploration Of Prostate Cancer Cells: The Significance Of Active Herv, Dakota Shepherd

Student Scholar Showcase

The second most common cancer in men is prostate cancer. Prostate cancer is traditionally diagnosed by a digital rectal exam. Blood tests can also be used to test for PSA (prostate-specific antigen). These two methods can be used together but can sometimes provide both false negative and false positive results. A new method of testing for prostate cancer could prove to be beneficial. Previous studies have shown that active HERV sequences have been identified in some cancers, including prostate cancer. We hypothesize that the presence of active HERV in prostate cancer lines is significant. In this study, rabbit polyclonal antibodies …

Splice-Altering Variant In Col11a1 As A Cause Of Nonsyndromic Hearing Loss Dfna37., Kevin T. Booth, James W. Askew, Zohreh Talebizadeh, Patrick L M Huygen, James Eudy, Judith Kenyon, Denise Hoover, Michael S. Hildebrand, Katherine R. Smith, Melanie Bahlo, William J. Kimberling, Richard J H Smith, Hela Azaiez, Shelley D. Smith

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family.

METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family.

RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 …

The Pharmabiotic For Phenylketonuria: Development Of A Novel Therapeutic, Chloé Elizabeth Lebegue

Senior Theses

Phenylketonuria, now known as phenylalanine hydroxylase (PAH) deficiency, is a genetic disorder of metabolism affecting approximately one in every 15,000 infants born in the United States. Patients have nonfunctional PAH enzyme secondary to one or more genetic mutations. The enzyme deficit results in destructive supraphysiologic blood phenylalanine levels upon consumption of the essential dietary amino acid phenylalanine. Current standards of care mitigate signs and symptoms of the disorder, but do not approach a cure. The methods for creating a prototype pharmabiotic as an innovative treatment strategy for PAH deficiency are described herein.

DNA molecular cloning techniques were utilized to engineer …

H3k27m Induces Defective Chromatin Spread Of Prc2-Mediated Repressive H3k27me2/Me3 And Is Essential For Glioma Tumorigenesis., Ashot S. Harutyunyan, Brian Krug, Haifen Chen, Simon Papillon-Cavanagh, Michele Zeinieh, Nicolas De Jay, Shriya Deshmukh, Carol C L Chen, Jad Belle, Leonie G. Mikael, Dylan M. Marchione, Rui Li, Hamid Nikbakht, Bo Hu, Gael Cagnone, Warren A. Cheung, Abdulshakour Mohammadnia, Denise Bechet, Damien Faury, Melissa K. Mcconechy, Manav Pathania, Siddhant U. Jain, Benjamin Ellezam, Alexander G. Weil, Alexandre Montpetit, Paolo Salomoni, Tomi Pastinen, Chao Lu, Peter W. Lewis, Benjamin A. Garcia, Claudia L. Kleinman, Nada Jabado, Jacek Majewski

Manuscripts, Articles, Book Chapters and Other Papers

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on …