Integrative view on how erythropoietin signaling controls transcription patterns in erythroid cells

Abstract

Purpose of review: Erythropoietin (EPO) is necessary and sufficient to trigger dynamic transcriptional patterns that drive the differentiation of erythroid precursor cells into mature, enucleated red cells. Because the molecular cloning and Food and Drug Administration approval for the therapeutic use of EPO over 30 years ago, a detailed understanding of how EPO works has advanced substantially. Yet, the precise epigenetic and transcriptional mechanisms by which EPO signaling controls erythroid expression patterns remains poorly understood. This review focuses on the current state of erythroid biology in regards to EPO signaling from human genetics and functional genomics perspectives.

Recent findings: The goal of this review is to provide an integrative view of the gene regulatory underpinnings for erythroid expression patterns that are dynamically shaped during erythroid differentiation. Here, we highlight vignettes connecting recent insights into a genome-wide association study linking an EPO mutation to anemia, a study linking EPO-signaling to signal transducer and activator of transcription 5 (STAT5) chromatin occupancy and enhancers, and studies that examine the molecular mechanisms driving topological chromatin organization in erythroid cells.

Summary: The genetic, epigenetic, and gene regulatory mechanisms underlying how hormone signal transduction influences erythroid gene expression remains only partly understood. A detailed understanding of these molecular pathways and how they intersect with one another will provide the basis for novel strategies to treat anemia and potentially other hematological diseases. As new regulators and signal transducers of EPO-signaling continue to emerge, new clinically relevant targets may be identified that improve the specificity and effectiveness of EPO therapy.

FIGURE 1

Integrative model illustrating how transcription factors, enhancers, and chromatin looping work together to recruit Pol II to promoters during erythropoiesis. The erythroid master regulator transcription factors (GATA1, KLF1, and TAL1) predominantly bind to enhancers (denoted by purple rectangles) in various assemblages in conjunction with accessory proteins, including E2A, LDB1, and LMO2. E2A is a member of the E protein family of helix-loop-helix transcription factors that forms a heterodimer with TAL1 to bind DNA. With LMO2 tethering LDB1 to erythroid transcription factors, LDB1 facilitates higher order complex assembly and chromatin looping interactions via LDB1 homodimerization [8]. EPO-EPOR-JAK2 signaling directly activates STAT5, which integrates with the master regulators by cooccupying several hundred GATA1 bound enhancers [34^■■]. Transcription factors and enhancers interact within the confines of topologically associated chromatin domains that are structurally held together by CTCF and cohesin, as well as other regulatory and structural factors.