Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell–based hematological malignancies.

中文翻译：

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HDAC7-TET2 表观遗传轴在早期 B 淋巴细胞发育过程中至关重要

在 B 淋巴细胞发育过程中细胞分化的每个阶段，正确的 B 细胞身份严重依赖于严格控制的表观基因组环境。我们之前将 HDAC7 确定为早期 B 细胞发育的重要调节因子，它的缺失导致 pro-B 到前 B 细胞过渡的剧烈阻滞。最近，我们证明了婴儿 pro-B-ALL 中 HDAC7 的缺失与较差的预后相关。在这里，我们描述了 HDAC7 调节早期 B 细胞发育的分子机制。我们发现 HDAC7 缺乏会导致整体染色质去浓缩、组蛋白标记沉积并解除对其他表观遗传调节因子和移动元件的调节。具体来说，HDAC7 的缺失会诱导 TET2 表达，从而促进 DNA 5-羟甲基化和染色质去浓缩。HDAC7 缺乏还会导致 microRNA 和 LINE-1 转座因子的异常表达。这些发现揭示了 HDAC7 缺失或失调可能导致基于 B 细胞的血液恶性肿瘤的机制。