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组蛋白甲基转移酶 DOT1L 在 B 细胞分化过程中控制特定状态的身份。

Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation.

机构信息

Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan.

出版信息

EMBO Rep. 2021 Feb 3;22(2):e51184. doi: 10.15252/embr.202051184. Epub 2021 Jan 7.

DOI:10.15252/embr.202051184
PMID:33410591
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7857439/
Abstract

Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B-cell fate remain unclear. Here, we identified a role for the histone H3K79 methyltransferase DOT1L in controlling B-cell differentiation. Mouse B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells in which Dot1L was deleted showed aberrant differentiation and prematurely acquired plasma cell characteristics. Similar results were obtained when DOT1L was chemically inhibited in mature B cells in vitro. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L indirectly supports the repression of an anti-proliferative plasma cell differentiation program by maintaining the repression of Polycomb Repressor Complex 2 (PRC2) targets. Our findings show that DOT1L is a key modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B-cell naivety and GC B-cell differentiation.

摘要

幼稚外周 B 细胞分化为终末分化的浆细胞的特征是表观遗传改变，但控制 B 细胞命运的表观遗传机制仍不清楚。在这里，我们确定了组蛋白 H3K79 甲基转移酶 DOT1L 在控制 B 细胞分化中的作用。缺乏 Dot1L 的小鼠 B 细胞无法在体内建立生发中心 (GC) 和正常的体液免疫反应。在体外，缺失 Dot1L 的活化 B 细胞表现出异常分化，并过早获得浆细胞特征。当 DOT1L 在体外的成熟 B 细胞中被化学抑制时，也得到了类似的结果。从机制上讲，联合表观基因组学和转录组学分析表明，DOT1L 促进了促增殖、促 GC 程序的表达。此外，DOT1L 通过维持多梳抑制复合物 2 (PRC2) 靶标的抑制，间接支持抑制抗增殖浆细胞分化程序。我们的研究结果表明，DOT1L 是 B 细胞核心转录和表观遗传景观的关键调节剂，建立了一个表观遗传障碍，保证了 B 细胞的幼稚性和 GC B 细胞的分化。

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