Faculty Candidate Seminar 2/11/16:

Title: “Screening for epigenetic regulators of hematopoiesis”

Speaker: 
Dr. Katie Kathrein, Boston Children’s Hospital, Zon Laboratory

Abstract: 
Hematopoietic stem cells (HSCs) serve as the foundation of the immune system and are capable of self-renewal and differentiation into all mature immune cell lineages. Regulation of this process is in part achieved by factors that orchestrate chromatin structure and establish an epigenetic code for hematopoiesis. To generate a complete compendium of factors that regulate this epigenetic code in HSCs, I have undertaken the first large-scale in vivo reverse genetic screen targeting chromatin factors. Using morpholinos against 488 chromatin remodeling factors to inhibit target gene expression, I identified 29 genes that alter HSC marker expression upon knockdown. A subset of these identified factors belong to complexes already known to regulate hematopoiesis, such as members of the polycomb, NuRD, and trithorax complexes. Other factors belong to complexes such as the Hbo1 complex, which has no known role in hematopoiesis. Four members of this complex, Ing4, Phf16 (Jade3), Hbo1, and Brd1, were identified in the screen. Using ChIP-seq for ING4 in human CD34+ blood progenitor cells, I found that ING4 is bound to many regulators of blood development including c-myb, lmo2, runx1 and ikaros. Previous work has shown that ING4 can regulate the transcription factor NF-kB through sequestration of the RELA component of NF-kB at target loci. ING4 is also bound to several NF-kB target genes in CD34+ cells. As ING4 negatively regulates NF-kB, this suggests that loss of ING4 results in an overabundance of NF-kB signaling. Both zebrafish and mice lacking Ing4 have altered hematopoiesis and increased NF-kB target gene expression and HSCs from Ing4 null mice don’t perform in the same manner as their wild-type counterparts in competitive transplantation assays. As well, loss of both Ing4 and NF-kB can rescue HSC specification in zebrafish. These results suggest a novel mechanism for HSC regulation by Ing4 and the Hbo1 complex through regulation of inflammatory signaling.

Dr. Russell Hill, Ph.D.