Open Seminars of the Research Group on

 

Stochasticity and Control in the Dynamics and Diversity of Immune Repertories: an Example of Multi-Cellular Co-Operation

 

Tuesday, May 16, 2017, 14:00

at the Israel Institute for Advanced Studies, Room 128

 

 

Epigenetics and expression heterogeneity in mouse embryonic stem cells

 

Eran Meshorer (HUJI) 

 

Pluripotent self-renewing embryonic stem cells (ESCs) have been the focus of a growing number of high-throughput experiments, revealing the genome-wide locations of hundreds of transcription factors and histone modifications. While most of these datasets were used in a specific context, all datasets combined offer a comprehensive view of chromatin characteristics and regulatory elements that govern cell states. We recently assembled all published genome-wide ChIP experiments in mouse and human ESCs into a searchable database and webtool allowing epigenomic analysis (Livyatan et al., Cell Stem Cell, 2015). Using these hundreds of datasets in ESCs, we generated colocalization maps of chromatin proteins and modifications, and built a discovery pipeline for regulatory proteins of gene families. We define alternative promoters of pluripotency factors, provide an expanded epigenetic profile for lincRNA genes beyond the basal ‘‘K4–K36’’ and detect subclasses of lincRNAs that may be indicative of their potential function, and offer an Enhancer Finder function which scans the upstream region of any given gene for potential regulatory elements. By comparing genome-wide binding data with over-expression and knockdown analysis of hundreds of genes, we discovered that the pluripotency-related factor Nr5a2 separates mitochondrial from cytosolic ribosomal genes, regulating their expression. We further show that genes with a common chromatin profile are enriched for distinct Gene Ontology (GO) categories. By combining these data with single cell RNA-sequencing (scRNA-seq) data, we were able to assign an epigenomic signature for heterogeneous and stable genes in ESCs. Our approach can be generalized to reveal common regulators of any gene group; discover novel gene families, and identify common genomic elements based on shared chromatin features. 

 

 

Related Research Questions

 

  1. Do epigenetic profiles of gene families provide functional information beyond expression?
  2. Is expression heterogeneity regulated at the epigenetic level?
  3. Can we systematically identify transcription factors regulating heterogeneous expression?
 

 

Suggested Reading

 

Studying lineage decision-making in vitro: emerging concepts and novel tools.
Semrau S and van Oudenaarden A (2015) 
Annu Rev Cell Dev Biol.31:317-45
 
BindDB: An integrated database and webtool platform for "Reverse-ChIP" epigenomic analysis.
Livyatan I, Aaronson Y, Gokhman D, Ashkenazi R, Meshorer E (2015) 
Cell Stem Cell, 17(6):647-8
 
Systematic identification of gene family regulators in mouse and human embryonic stem cells. 
Aaronson Y, Livyatan I, Gokhman D, Meshorer E (2016) 
Nucleic Acids Res.,44(9):4080-9
 

 

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