Epigenetic and genetic mechanisms in red cell biology.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
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.
Kyle J
KJ
Hewitt
Rajendran
R
Sanalkumar
Kirby D
KD
Johnson
Sunduz
S
Keles
Emery H
EH
Bresnick
D057890:Epigenomics; D004912:Erythrocytes / Q000502:physiology*; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D014157:Transcription Factors / Q000502:physiology*
D014157:Transcription Factors