红细胞的正常终末发育过程中须伴随染色质压缩现象，但其机制仍不明确。 我们的前期研究首次使用HiC检测红细胞终末分化过程中全基因组范围染色质的互作情况，结果表明染色质发生高度压缩，远端互作比例上调，拓扑相关结构域(TAD)边界发生弱化；有研究报道称核磷蛋白家族成员NPM1能够通过调控Histone H1在染色质上的结合影响转录，而H1的缺失表达可导致染色质的松散状态。我们发现NPM1在终末分化阶段下调，而过表达NPM1能够显著抑制红细胞终末分化中细胞核的缩小。NPM1经常在MDS中产生突变而失去功能，但NPM1非突变型的MDS中其表达显著高于正常骨髓样品，因此NPM1很可能在MDS中导致红细胞终末分化异常，影响正常造血。我们的研究中将阐明红系终末发育中的染色质压缩是如何受到NPM1与H1的调控、其作用与异染色质重构的相关性，以及NPM1是否可作为潜在的缓解MDS，促进其红系发育的靶点。

Chromatin compaction occurs during the terminal development of red blood cells, and this process is required for normal development of red blood cells, but the underlying molecular mechanism remains unclear. .Our pilot study demonstrated the genome-wide chromatin interaction changes during terminal erythroid differentiation by Hi-C for the first time. This result showed that the chromatin became highly compressed as terminal differentiation progresses. Interestingly, the distal interactions of chromatin were upregulated, while the boundaries of topologically related domains (TAD) were weakened. .Previous studies have found that NPM1, a member of the nucleophosmin family, can affect transcription by regulating the binding of Histone H1 on chromatin, and the loss of H1 expression can lead to loosened state of chromatin. We found that NPM1 is down-regulated during the terminal differentiation, and overexpression of NPM1 significantly prevents nuclear condensation during the terminal differentiation of red blood cells. Loss-of-function mutations of NPM1 are often observed in MDS, but the expression of NPM1 in MDS without NPM1 mutations is significantly higher than that of normal bone marrow samples, so we suspect that NPM1 is likely to cause abnormal red blood cell terminal differentiation in MDS, and affect normal hematopoiesis. Key questions remain unanswered: how is NPM1 down-regulated during the development of red blood cells? How do NPM1 and H1 regulate the compression of the nucleus during terminal erythropoiesis? Is heterochromatin remodeling involved in this process? Are there hot spots of chromatin compression during terminal erythroid differentiation? Is NPM1 a potential target for mitigating MDS via promoting erythroid differentiation? We will investigate and address these questions in the proposed project.