Locus-specific editing of histone modifications at endogenous enhancers using programmable TALE-LSD1 fusions

Details

• Alternative Title:
  Nat Biotechnol
• Personal Author:
  Mendenhall, Eric M. ; Williamson, Kaylyn E. ; Reyon, Deepak ; Zou, James Y. ; Ram, Oren ; Joung, J. Keith ; Bernstein, Bradley E.
• Description:
  Mammalian gene regulation is dependent on tissue-specific enhancers that can act across large distances to influence transcriptional activity. Mapping experiments have identified hundreds of thousands of putative enhancers whose functionality is supported by cell type-specific chromatin signatures and striking enrichments for disease-associated sequence variants. However, these studies did not address the in vivo functions of the putative elements or their chromatin states and did not determine which genes, if any, a given enhancer regulates. Here we present a strategy to investigate endogenous regulatory elements by selectively altering their chromatin state using programmable reagents. Transcription activator-like (TAL) effector repeat domains fused to the LSD1 histone demethylase efficiently remove enhancer-associated chromatin modifications from target loci, without affecting control regions. We find that inactivation of enhancer chromatin by these fusion proteins frequently causes downregulation of proximal genes, revealing enhancer target genes. Our study demonstrates the potential of epigenome editing tools to characterize an important class of functional genomic elements.
• Subjects:
  Article Chromatin Enhancer Elements, Genetic Histones Mutagenesis, Site-Directed Polymorphism, Single Nucleotide Promoter Regions, Genetic Regulatory Elements, Transcriptional
• Source:
  Nat Biotechnol. 31(12):1133-1136.
• Pubmed ID:
  24013198
• Pubmed Central ID:
  PMC3858395
• Document Type:
  Journal Article
• Funding:
  DP1 GM105378/DP/NCCDPHP CDC HHS/United States ; DP1 GM105378/GM/NIGMS NIH HHS/United States ; P50 HG005550/HG/NHGRI NIH HHS/United States ; U01 ES017155/ES/NIEHS NIH HHS/United States ; U01 ES017155/ES/NIEHS NIH HHS/United States ; U54 HG004570/HG/NHGRI NIH HHS/United States ; U54 HG004570/HG/NHGRI NIH HHS/United States ; U54 HG006991/HG/NHGRI NIH HHS/United States ; U54 HG006991/HG/NHGRI NIH HHS/United States ; Howard Hughes Medical Institute/United States
• Volume:
  31
• Issue:
  12
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:515785e8e12f7961eaecf3b3b6586c3a05c309d22747b57def279e4b2d47a6c5
• Download URL:
  https://stacks.cdc.gov/view/cdc/23418/cdc_23418_DS1.pdf
• File Type:
  [PDF - 1.14 MB ]