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

Document Type

Article

Publication Date

2-2020

Keywords

JMG

JAX Source

Exp Hematol 2020 Feb; 82:43-52.e4

Volume

82

First Page

43

Last Page

52

ISSN

1873-2399

PMID

32014431

DOI

https://doi.org/10.1016/j.exphem.2020.01.014

Grant

AG038070, HD007065

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.

Comments

We thank Tina Mujica, Jennifer SanMiguel,

Olivia Erickson, Tara Murphy and Kaiden Waldron-Francis

for technical help and experimental and laboratory

support. We thank members of Trowbridge Laboratory,

Christopher Baker, Luanne Peters, Derry Roopenian, and

Dustin Updike for helpful discussions. We acknowledge

Mingyang Lu and Vivek Kohar for computational assistance.

We thank Genetic Engineering Technologies,

Microscopy, Genome Technologies, and Flow Cytometry scientific services at The Jackson Laboratory for their contribution to these studies.

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