Lymphocyte Development and Disease Group, Josep Carreras Leukaemia Research Institute, 08916 Badalona, Spain.
Cellular Differentiation Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via 199, 08908 L'Hospitalet, Barcelona, Spain.
Nucleic Acids Res. 2022 Aug 26;50(15):8471-8490. doi: 10.1093/nar/gkac619.
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.
在 B 淋巴细胞发育过程中细胞分化的每个阶段，正确的 B 细胞身份都取决于严格控制的表观基因组景观。我们之前发现 HDAC7 是早期 B 细胞发育的必需调节剂，其缺失会导致前 B 细胞向 pre-B 细胞过渡的严重阻滞。最近，我们证明了婴儿期前 B-ALL 中 HDAC7 的缺失与更差的预后相关。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 缺乏会导致全局染色质去凝聚、组蛋白标记的沉积，并使其他表观遗传调节剂和可移动元件失活。具体来说，HDAC7 的缺失会诱导 TET2 的表达，从而促进 DNA 5-羟甲基化和染色质去凝聚。HDAC7 的缺乏还会导致 microRNA 和 LINE-1 转座元件的异常表达。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。
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