Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors

bioRxiv - Developmental Biology Pub Date : 2024-09-17 DOI:10.1101/2024.09.16.613227

Kutay Karatepe, Bruna Mafra de Faria, jian zhang, Xinyue Chen, Hugo Pinto, Dmitry Fyodorov, Esen Sefik, Michael Willcockson, Richard Flavell, Arthur I Skoultchi, Shangqin Guo

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Abstract

Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. HSPCs expressing H1.0 from a doxycycline (dox) inducible transgene favor the lymphoid fate, display strengthened nucleosome organization and reduced chromatin accessibility at genomic regions hosting key myeloid fate drivers. The transcription factor Hlf is located in one of such regions, where chromatin accessibility and gene expression is reduced in H1.0high HSPCs. Furthermore, H1.0 protein in HSPCs can decreases in an aspartyl protease dependent manner, a process enhanced in response to interferon alpha signaling. Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work uncovers a point of intervention to mitigate myeloid skewed hematopoiesis.

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连接组蛋白调节多能造血干细胞和祖细胞的髓系与淋巴系分叉

随着衰老或衰竭，多能造血干细胞和祖细胞（HSPCs）会出现髓系偏向分化。造成这种命运偏向的分子机制仍不清楚。在这里，我们报告了连接组蛋白调节HSPC在淋巴细胞与骨髓细胞分叉处的命运选择。通过多西环素（dox）诱导转基因表达H1.0的HSPC更倾向于淋巴细胞命运，在承载关键髓系命运驱动因子的基因组区域显示出强化的核小体组织和降低的染色质可及性。转录因子 Hlf 位于其中一个区域，在 H1.0 高的 HSPC 中，该区域的染色质可及性和基因表达均降低。此外，HSPCs 中的 H1.0 蛋白会以天冬氨酰蛋白酶依赖的方式减少，这一过程在干扰素α信号的作用下会增强。天冬氨酰蛋白酶抑制剂能保持内源性 H1.0 水平，并促进野生型 HSPCs 的淋巴命运。因此，我们的研究发现了一个干预点，可以减轻骨髓偏斜造血。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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bioRxiv - Developmental Biology

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