Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts
Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts
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DOI：
10.1038/s41419-020-2500-6
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发表时间：
2020-05-04
影响因子：
9
通讯作者：
Renaud, Stephen J.
中科院分区：
文献类型：
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作者：
Bhattad, Gargi Jaju;Jeyarajah, Mariyan J.;Renaud, Stephen J.
当几个细胞联合收割机结合形成多核聚集体（合胞体）时，细胞融合发生。在人类胎盘中，合胞滋养层（syncytiotrophoblast）层形成母体和胎儿组织之间的主要界面，促进营养和气体交换，并产生对妊娠至关重要的激素。合胞体滋养层的发育是由细胞滋养层的祖细胞分化而成，然后融合到合胞体滋养层中。分化与染色质重塑和基因表达的特异性变化相关，至少部分由组蛋白乙酰化介导。然而，人类细胞滋养层细胞分化和融合的表观遗传调控知之甚少。在这项研究中，我们发现人类合体滋养层细胞的发育与多个核心组蛋白残基的脱乙酰化有关。染色质免疫沉淀测序显示，在分化过程中组蛋白H3乙酰化的动态变化的染色体区域。这些包括含有与细胞滋养层分化典型相关的基因（TEAD 4，TP 63，OVOL1，CGB）的区域，以及在滋养层发育和功能中具有新调控作用的近基因，如LHX 4和SYDE 1。使用药理学和遗传学方法预防组蛋白去乙酰化抑制滋养层融合，支持这一过程对滋养层分化的关键作用。最后，我们确定了组蛋白脱乙酰酶（HDAC）HDAC 1和HDAC 2作为驱动细胞滋养层分化的关键介质。总的来说，这些研究结果提供了新的见解，在人类胎盘发育过程中滋养层融合的表观遗传机制。
Cell fusion occurs when several cells combine to form a multinuclear aggregate (syncytium). In human placenta, a syncytialized trophoblast (syncytiotrophoblast) layer forms the primary interface between maternal and fetal tissue, facilitates nutrient and gas exchange, and produces hormones vital for pregnancy. Syncytiotrophoblast development occurs by differentiation of underlying progenitor cells called cytotrophoblasts, which then fuse into the syncytiotrophoblast layer. Differentiation is associated with chromatin remodeling and specific changes in gene expression mediated, at least in part, by histone acetylation. However, the epigenetic regulation of human cytotrophoblast differentiation and fusion is poorly understood. In this study, we found that human syncytiotrophoblast development was associated with deacetylation of multiple core histone residues. Chromatin immunoprecipitation sequencing revealed chromosomal regions that exhibit dynamic alterations in histone H3 acetylation during differentiation. These include regions containing genes classically associated with cytotrophoblast differentiation (TEAD4, TP63, OVOL1, CGB), as well as near genes with novel regulatory roles in trophoblast development and function, such as LHX4 and SYDE1. Prevention of histone deacetylation using both pharmacological and genetic approaches inhibited trophoblast fusion, supporting a critical role of this process for trophoblast differentiation. Finally, we identified the histone deacetylases (HDACs) HDAC1 and HDAC2 as the critical mediators driving cytotrophoblast differentiation. Collectively, these findings provide novel insights into the epigenetic mechanisms underlying trophoblast fusion during human placental development.