Discovering How Heme Controls Genome Function Through Heme-omics
Discovering How Heme Controls Genome Function Through Heme-omics
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DOI：
10.1016/j.celrep.2020.107832
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发表时间：
2020-06-30
期刊：
影响因子：
8.8
通讯作者：
Bresnick, Emery H.
中科院分区：
文献类型：
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作者：
Liao, Ruiqi;Zheng, Ye;Bresnick, Emery H.
蛋白质集合通过建立、维持和解构细胞类型特异性染色体景观来控制基因组功能。过多的小分子协调细胞功能，因此可能将生理过程与基因组生物学联系起来。代谢酶和血红蛋白辅因子血红素诱导转录抑制因子Bach 1的蛋白水解，并在转录后调节基因表达。然而，血红素是否控制基因组功能广泛或通过规定的行动尚不清楚。使用转座酶可及染色质测序（ATAC-seq）测定，我们在缺乏增强子的野生型和突变型成红细胞中建立了血红素依赖性染色质图谱，增强子赋予正常血红素合成。融合染色质景观和转录组在亚生理血红素和血红素后救援细胞揭示了平行Bach 1依赖性和Bach 1独立的机制，目标血红素传感染色体热点。热点含有一个DNA基序，划分血红素调节的染色质和编码蛋白质的基因，这些蛋白质不知道是血红素调节的，包括代谢酶。血红素组学分析确定了一个重要的生化辅因子如何控制基因组功能和细胞生理学。
Protein ensembles control genome function by establishing, maintaining, and deconstructing cell-type-specific chromosomal landscapes. A plethora of small molecules orchestrate cellular functions and therefore may link physiological processes with genome biology. The metabolic enzyme and hemoglobin cofactor heme induces proteolysis of a transcriptional repressor, Bach1, and regulates gene expression post-transcriptionally. However, whether heme controls genome function broadly or through prescriptive actions is unclear. Using assay for transposase-accessible chromatin sequencing (ATAC-seq), we establish a heme-dependent chromatin atlas in wild-type and mutant erythroblasts lacking enhancers that confer normal heme synthesis. Amalgamating chromatin landscapes and transcriptomes in cells with sub-physiological heme and post-heme rescue reveals parallel Bach1-dependent and Bach1-independent mechanisms that target heme-sensing chromosomal hotspots. The hotspots harbor a DNA motif demarcating heme-regulated chromatin and genes encoding proteins not known to be heme regulated, including metabolic enzymes. The heme-omics analysis establishes how an essential biochemical cofactor controls genome function and cellular physiology.