aDepartment of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health bUW-Madison Blood Research Program, Carbone Cancer Center cDepartment of Biostatistics and Medical Informatics, Department of Statistics, Wisconsin Institutes for Medical Research, Madison, Wisconsin, USA.
Curr Opin Hematol. 2014 May;21(3):155-64. doi: 10.1097/MOH.0000000000000034.
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.
造血干细胞（HSCs）生成向造血谱系分化的祖细胞，这些祖细胞进一步成熟为红细胞，这一过程称为红细胞生成，其受到多种染色质修饰和重塑蛋白的调控。我们将重点关注表观遗传和遗传机制如何协同作用来建立红细胞的转录组，以及研究红细胞生成如何产生基因组原则。
反式作用因子结合到小的 DNA 基序（顺式元件）上，为特定染色质位点的调控复合物组装提供基础，因此产生独特的转录组。由于顺式元件通常非常小，给定元件的数千或数百万个拷贝存在于基因组中。染色质以依赖于上下文的方式限制因子的接近，顺式元件结合因子招募染色质调节剂，从而介导功能输出。在体内绘制基因座染色质属性、编辑基因组和对整个基因组进行测序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，这说明了遗传和表观遗传机制的融合。顺式元件在其内源基因座之外进行研究时，通常具有异位功能，需要进一步开发复杂的策略来识别非冗余顺式元件。易于操作的基因组编辑技术为解决这一问题提供了一种新方法。将遗传分析扩展到外显子和启动子之外，将产生大量与红细胞生物学和疾病相关的顺式元件改变。
