Distinct and overlapping DNMT1 interactions with multiple transcription factors in erythroid cells: Evidence for co-repressor functions.
Distinct and overlapping DNMT1 interactions with multiple transcription factors in erythroid cells: Evidence for co-repressor functions.
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DOI：
10.1016/j.bbagrm.2016.09.007
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发表时间：
2016-12
期刊：
影响因子：
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通讯作者：
Dimitris N. Papageorgiou;Elena Karkoulia;Alexandra Amaral-Psarris;P. Burda;Katarzyna E. Kolodziej;J. Demmers;J. Bungert;T. Stopka;J. Strouboulis
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文献类型：
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作者：
Dimitris N. Papageorgiou;Elena Karkoulia;Alexandra Amaral-Psarris;P. Burda;Katarzyna E. Kolodziej;J. Demmers;J. Bungert;T. Stopka;J. Strouboulis
DNMT1是维持DNA甲基转移酶，对哺乳动物胚胎发育和许多体细胞组织的细胞生长和分化至关重要。越来越多的证据也表明DNMT1通过与特定转录因子的相互作用抑制基因表达。在此之前，我们发现DNMT1是红细胞中TR2/TR4核受体异二聚体的一个相互作用的伙伴，参与了人红细胞成体阶段胎儿β型珠蛋白基因的发育沉默。在这里，我们通过使用生物素化标记方法扩展了这项工作，以表征小鼠红白血病细胞中的DNMT1蛋白复合物。我们发现新的DNMT1与几个造血转录因子相互作用，这些因子在红细胞分化中起重要作用，包括GATA1， GFI-1b和fog1。我们提供了DNMT1与特定转录因子形成不同蛋白亚复合物的证据，并提出存在与转录因子ZBP-89和ZNF143的“核心”DNMT1复合物，该复合物也存在于非造血细胞中。此外，我们确定了短（17a.a.）PCNA结合域（PBD）位于DNMT1的n端附近，是介导与本文描述的转录因子相互作用所必需的。最后，我们提供证据证明DNMT1作为ZBP-89和GATA1的共同抑制因子，通过PU.1和GATA1基因位点的上游调控元件起作用。
DNMT1 is the maintenance DNA methyltransferase shown to be essential for embryonic development and cellular growth and differentiation in many somatic tissues in mammals. Increasing evidence has also suggested a role for DNMT1 in repressing gene expression through interactions with specific transcription factors. Previously, we identified DNMT1 as an interacting partner of the TR2/TR4 nuclear receptor heterodimer in erythroid cells, implicated in the developmental silencing of fetal β-type globin genes in the adult stage of human erythropoiesis. Here, we extended this work by using a biotinylation tagging approach to characterize DNMT1 protein complexes in mouse erythroleukemic cells. We identified novel DNMT1 interactions with several hematopoietic transcription factors with essential roles in erythroid differentiation, including GATA1, GFI-1b and FOG-1. We provide evidence for DNMT1 forming distinct protein subcomplexes with specific transcription factors and propose the existence of a “core” DNMT1 complex with the transcription factors ZBP-89 and ZNF143, which is also present in non-hematopoietic cells. Furthermore, we identified the short (17a.a.) PCNA Binding Domain (PBD) located near the N-terminus of DNMT1 as being necessary for mediating interactions with the transcription factors described herein. Lastly, we provide evidence for DNMT1 serving as a co-repressor of ZBP-89 and GATA1 acting through upstream regulatory elements of the PU.1 and GATA1 gene loci.