Epigenetic and genetic mechanisms in red cell biology.
Epigenetic and genetic mechanisms in red cell biology.
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DOI：
10.1097/moh.0000000000000034
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发表时间：
2014-05
影响因子：
3.2
通讯作者：
Bresnick EH
中科院分区：
文献类型：
--
作者：
Hewitt KJ;Sanalkumar R;Johnson KD;Keles S;Bresnick EH
红细胞生成，其中造血干细胞（HSC）产生成熟为红细胞的谱系定型祖细胞，受到许多染色质修饰和重塑蛋白的调节。我们将专注于如何表观遗传和遗传机制网建立红细胞转录组和如何研究红细胞生成可以产生基因组的原则。反式作用因子与小DNA基序（顺式元件）的结合是调控复合物在特定染色质位点组装的基础，因此是独特的转录组。由于顺式元件通常非常小，因此给定元件的数千或数百万个拷贝存在于基因组中。染色质限制因素的访问在一个上下文依赖的方式，和顺式元件结合因子招募染色质调节介导的功能输出。绘制体内基因座的染色质属性、编辑基因组和测序全基因组的技术在发现与人类疾病相关的关键顺式元件方面具有变革性。顺式元件介导染色质靶向特异性，染色质调节剂决定顺式元件的可及性/功能，说明了遗传和表观遗传机制的融合。顺式元件往往异位功能时，研究其内源性位点外，和复杂的战略，以确定非冗余顺式元件需要进一步的发展。简单的基因组编辑技术为解决这一问题提供了一种新的方法。将遗传分析扩展到外显子和启动子之外，将产生丰富的顺式元件改变管道，对红细胞生物学和疾病具有重要意义。
Erythropoiesis, in which hematopoietic stem cells (HSCs) generate lineage-committed progenitors that mature into erythrocytes, is regulated by numerous chromatin modifying and remodeling proteins. We will focus on how epigenetic and genetic mechanisms mesh to establish the erythroid transcriptome and how studying erythropoiesis can yield genomic principles. Trans-acting factor binding to small DNA motifs (cis-elements) underlies regulatory complex assembly at specific chromatin sites, and therefore unique transcriptomes. As cis-elements are often very small, thousands or millions of copies of a given element reside in a genome. Chromatin restricts factor access in a context-dependent manner, and cis-element-binding factors recruit chromatin regulators that mediate functional outputs. Technologies to map chromatin attributes of loci in vivo, to edit genomes and to sequence whole genomes have been transformative in discovering critical cis-elements linked to human disease. Cis-elements mediate chromatin-targeting specificity, and chromatin regulators dictate cis-element accessibility/function, illustrating an amalgamation of genetic and epigenetic mechanisms. Cis-elements often function ectopically when studied outside of their endogenous loci, and complex strategies to identify nonredundant cis-elements require further development. Facile genome-editing technologies provide a new approach to address this problem. Extending genetic analyses beyond exons and promoters will yield a rich pipeline of cis-element alterations with importance for red cell biology and disease.