Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, USA; The Jackson Laboratory, Bar Harbor, ME, USA.
The Jackson Laboratory, Bar Harbor, ME, USA.
Exp Hematol. 2020 Feb;82:43-52.e4. doi: 10.1016/j.exphem.2020.01.014. Epub 2020 Feb 1.
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.
衰老的造血干细胞（HSCs）经历偏向谱系的启动和向髓系细胞分化。为了设计新的策略来可持续地改善老年个体的免疫功能，需要全面了解导致 HSC 衰老的基因调控机制。在这里，通过对表观遗传因子的靶向短发夹 RNA 筛选，发现组蛋白乙酰转移酶 Kat6b 调节造血祖细胞向髓系细胞的产生。在干细胞和祖细胞区室中，Kat6b 在长期（LT）-HSCs 中高度表达，并随着年龄的增长，在转录和蛋白水平上显著降低。在年轻的 LT-HSCs 中敲低 Kat6b 会导致体外和体内以牺牲红细胞为代价的偏向性产生髓系细胞。转录组分析鉴定出与衰老和巨噬细胞相关的基因特征富集，同时自我更新和多谱系启动特征的表达降低。总之，我们的工作确定 KAT6B 是造血分化的新型表观遗传调节剂，也是改善衰老免疫功能的靶点。
