Blood disease-causing and -suppressing transcriptional enhancers: general principles and GATA2 mechanisms.

摘要: Intensive scrutiny of human genomes has unveiled considerable genetic variation in coding and noncoding regions. In cancers, including those the hematopoietic system, genomic instability amplifies complexity functional consequences variation. Although elucidating how impacts protein-coding sequence is highly tractable, deciphering regions (genome reading), potential transcriptional-regulatory sequences, remains challenging. A crux this problem sheer abundance gene-regulatory motifs (cis elements) mediating protein-DNA interactions that are intermixed genome with thousands look-alike sequences lacking capacity to mediate proteins vivo. Furthermore, transcriptional enhancers harbor clustered cis elements, altering a single element within cluster enhancer function unpredictable. Strategies discover have been innovated, genetics can provide vital clues achieve goal. Germline or acquired mutations functionally critical (essential) enhancers, for example at GATA2 locus encoding master regulator hematopoiesis, linked pathologies. Given interindividual complex landscapes hematologic malignancies, corruption, creation, expropriation by new genes may not be exceedingly rare mechanisms underlying disease predisposition etiology. Paradigms arising from dissecting essential guide genome-reading strategies advance fundamental knowledge precision medicine applications. review, we our perspective general principles governing blood disease-linked GATA2-centric mechanisms.