GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia

Abstract

SUMMARY An enhancer with amalgamated E-box and GATA motifs (+9.5) controls expression of the regulator of hematopoiesis GATA-2. While similar GATA-2-occupied elements are common in the genome, occupancy does not predict function, and GATA-2-dependent genetic networks are incompletely defined. A “+9.5-like” element resides in an intron of Samd14 (Samd14-Enh) encoding a sterile alpha motif (SAM) domain protein. Deletion of Samd14-Enh in mice strongly decreased Samd14 expression in bone marrow and spleen. Although steady-state hematopoiesis was normal, Samd14-Enh-/- mice died in response to severe anemia. Samd14-Enh stimulated Stem Cell Factor/c-Kit signaling, which promotes erythrocyte regeneration. Anemia activated Samd14-Enh by inducing enhancer components and enhancer chromatin accessibility. Thus, a GATA-2/anemia-regulated enhancer controls expression of a SAM domain protein that confers survival in anemia. We propose that Samd14-Enh and an ensemble of anemia-responsive enhancers are essential for erythrocyte regeneration in stress erythropoiesis, a vital process in pathologies including β-thalassemia, myelodysplastic syndrome and viral infection.

Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond

“…GATA2-and anemia-activated enhancers control expression of selective erythrocyte regeneration regulators and non-selective erythropoiesis regulators. (A) Anemia induces Epo production and increases Scl/TAL1 and GATA2 levels, all of which contribute to GATA2-and anemia-activated (G2A) enhancer activation (Hewitt et al, 2017). Although the precise mechanism whereby Epo-EpoR signaling contributes to enhancer activation has not been established, it is likely that this involves direct actions on transcription factors and chromatin constituents.…”

“…Other stress erythropoiesis circuits: deciphering the GATA factorregulated transcriptome A recent genomic analysis of cis-regulatory elements resembling the +9.5 enhancer mediating GATA2 function at the Gata2 locus has described new components of the GATA2-regulated HSPC cistrome (Hewitt et al, 2016(Hewitt et al, , 2015. A subset of these cis-elements constitutes GATA2-and anemia-activated (G2A) enhancers (Hewitt et al, 2017). One of these G2A enhancers (Samd14 Enh) mediates GATA2-dependent activation of Samd14, which is predicted to encode an unstudied member of a large protein family (Kim and Bowie, 2003) with the common attribute of harboring a sterile α motif (SAM) domain.…”

“…Loss-of-function studies with mouse fetal liver hematopoietic progenitors have provided evidence that Samd14 increases progenitors and facilitates Kit signaling (Hewitt et al, 2015). The targeted deletion of Samd14 Enh in mice abrogates Samd14 expression in fetal liver and in bone marrow hematopoietic progenitors and erythroid precursors without affecting its expression in brain (Hewitt et al, 2017). Although the resultant mutant mice have no detectable developmental or steady-state hematopoietic defects, they die in response to severe phenylhydrazine-induced anemia.…”

“…There is also much to be learned regarding mechanisms that function upstream of GATA2 and GATA1 and control their expression at the transcriptional level, as well as the translational and post-translational modes of regulating their activities. GATA2 not only regulates Kit expression, but also facilitates Kit signaling through induction of Samd14 expression (Hewitt et al, 2015(Hewitt et al, , 2016(Hewitt et al, , 2017. This circuit can be integrated into that of BMP4 signaling, in which BMP4 induces Gata2 expression (Friedle and Knöchel, 2002;Lugus et al, 2007).…”

Sterile α-motif domain requirement for cellular signaling and survival

“…Erythrocyte developmental mechanisms can differ during embryogenesis, adult homeostasis, and regenerative responses to injury or stress (1,2). In anemia, the increased erythropoiesis demand is met by augmented erythroid progenitor activity in the bone marrow or at extramedullary sites (3)(4)(5)(6). A cell population termed "stress erythroid progenitors" respond to diverse anemia-dependent paracrine signals, including erythropoietin (Epo) and stem cell factor (SCF), to induce rapid expansion and differentiation, thereby re-establishing homeostasis (7).…”