Aging-associated decrease in the histone acetyltransferase KAT6B is linked to altered hematopoietic stem cell differentiation

Exp Hematol. 2020 Feb;82:43-52.e4. doi: 10.1016/j.exphem.2020.01.014. Epub 2020 Feb 1.

Abstract

Aged hematopoietic stem cells (HSCs) undergo biased lineage priming and differentiation toward production of myeloid cells. A comprehensive understanding of gene regulatory mechanisms causing HSC aging is needed to devise new strategies to sustainably improve immune function in aged individuals. Here, a focused short hairpin RNA screen of epigenetic factors reveals that the histone acetyltransferase Kat6b regulates myeloid cell production from hematopoietic progenitor cells. Within the stem and progenitor cell compartment, Kat6b is highly expressed in long-term (LT)-HSCs and is significantly decreased with aging at the transcript and protein levels. Knockdown of Kat6b in young LT-HSCs causes skewed production of myeloid cells at the expense of erythroid cells both in vitro and in vivo. Transcriptome analysis identifies enrichment of aging and macrophage-associated gene signatures alongside reduced expression of self-renewal and multilineage priming signatures. Together, our work identifies KAT6B as a novel epigenetic regulator of hematopoietic differentiation and a target to improve aged immune function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Aging / pathology
  • Animals
  • Cell Differentiation*
  • Epigenesis, Genetic
  • Erythroid Cells / enzymology*
  • Erythroid Cells / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic*
  • Gene Knockout Techniques
  • Histone Acetyltransferases / biosynthesis*
  • Histone Acetyltransferases / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Myeloid Progenitor Cells / enzymology*
  • Myeloid Progenitor Cells / pathology
  • Transcriptome

Substances

  • Histone Acetyltransferases
  • Kat6b protein, mouse