A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.

Aging-associated decrease in the histone acetyltransferase KAT6B is linked to altered hematopoietic stem cell differentiation.

Aged hematopoietic stem cells (HSCs) undergo biased lineage priming and differentiation toward production of myeloid cells. A comprehensive understanding of gene regulatory mechanisms causing HSC aging is needed to devise new strategies to sustainably improve immune function in aged individuals. Here, a focused short hairpin RNA screen of epigenetic factors reveals that the histone acetyltransferase Kat6b regulates myeloid cell production from hematopoietic progenitor cells. Within the stem and progenitor cell compartment, Kat6b is highly expressed in long-term (LT)-HSCs and is significantly decreased with aging at the transcript and protein levels. Knockdown of Kat6b in young LT-HSCs causes skewed production of myeloid cells at the expense of erythroid cells both in vitro and in vivo. Transcriptome analysis identifies enrichment of aging and macrophage-associated gene signatures alongside reduced expression of self-renewal and multilineage priming signatures. Together, our work identifies KAT6B as a novel epigenetic regulator of hematopoietic differentiation and a target to improve aged immune function.

The Mediator of Hematopoietic Stem Cell Homeostasis.

Mechanisms establishing and maintaining promoter-enhancer interactions in hematopoietic stem cells (HSCs) to maintain stem cell identity are not fully understood. In this issue of Cell Stem Cell, Aranda-Orgilles et al. (2016) describe a role for a member of the Mediator complex in maintaining HSC-specific enhancers and hematopoietic homeostasis.

Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging.

Declining immune function with age is associated with reduced lymphoid output of hematopoietic stem cells (HSCs). Currently, there is poor understanding of changes with age in the heterogeneous multipotent progenitor (MPP) cell compartment, which is long lived and responsible for dynamically regulating output of mature hematopoietic cells. In this study, we observe an early and progressive loss of lymphoid-primed MPP cells (LMPP/MPP4) with aging, concomitant with expansion of HSCs. Transcriptome and in vitro functional analyses at the single-cell level reveal a concurrent increase in cycling of aging LMPP/MPP4 with loss of lymphoid priming and differentiation potential. Impaired lymphoid differentiation potential of aged LMPP/MPP4 is not rescued by transplantation into a young bone marrow microenvironment, demonstrating cell-autonomous changes in the MPP compartment with aging. These results pinpoint an age and cellular compartment to focus further interrogation of the drivers of lymphoid cell loss with aging.

DNA damage induces targeted, genome-wide variation of poly(A) sites in budding yeast.

Systemic response to DNA damage and other stresses is a complex process that includes changes in the regulation and activity of nearly all stages of gene expression. One gene regulatory mechanism used by eukaryotes is selection among alternative transcript isoforms that differ in polyadenylation [poly(A)] sites, resulting in changes either to the coding sequence or to portions of the 3' UTR that govern translation, stability, and localization. To determine the extent to which this means of regulation is used in response to DNA damage, we conducted a global analysis of poly(A) site usage in Saccharomyces cerevisiae after exposure to the UV mimetic, 4-nitroquinoline 1-oxide (4NQO). Two thousand thirty-one genes were found to have significant variation in poly(A) site distributions following 4NQO treatment, with a strong bias toward loss of short transcripts, including many with poly(A) sites located within the protein coding sequence (CDS). We further explored one possible mechanism that could contribute to the widespread differences in mRNA isoforms. The change in poly(A) site profile was associated with an inhibition of cleavage and polyadenylation in cell extract and a decrease in the levels of several key subunits in the mRNA 3'-end processing complex. Sequence analysis identified differences in the cis-acting elements that flank putatively suppressed and enhanced poly(A) sites, suggesting a mechanism that could discriminate between variable and constitutive poly(A) sites. Our analysis indicates that variation in mRNA length is an important part of the regulatory response to DNA damage.