Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation

Nucleic Acids Res. 2016 Sep 6;44(15):7173-88. doi: 10.1093/nar/gkw327. Epub 2016 May 3.

Abstract

The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a, an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult β-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Nuclear / metabolism
  • Cell Lineage* / genetics
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • Chromatin Immunoprecipitation
  • Erythroblasts / cytology
  • Erythroblasts / metabolism
  • Erythrocyte Count
  • Erythrocytes / cytology*
  • Erythrocytes / metabolism
  • Erythropoiesis* / genetics
  • Female
  • Gene Expression Regulation / genetics*
  • Hemoglobins / metabolism
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Male
  • Methylation
  • Mice
  • Mice, Knockout
  • Micrococcal Nuclease / metabolism
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • Spleen / cytology
  • Transcription Factors / metabolism
  • Upstream Stimulatory Factors / metabolism

Substances

  • Antigens, Nuclear
  • Chromatin
  • Hemoglobins
  • Histones
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Transcription Factors
  • USF1 protein, human
  • Upstream Stimulatory Factors
  • fetal Alzheimer antigen
  • Histone-Lysine N-Methyltransferase
  • Nsccn1 protein, mouse
  • Setd1A protein, human
  • Micrococcal Nuclease
  • Lysine