JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells

Abstract

Lifelong multilineage hematopoiesis critically depends on rare hematopoietic stem cells (HSCs) that reside in the hypoxic bone marrow microenvironment. Although the role of the canonical oxygen sensor hypoxia-inducible factor prolyl hydroxylase has been investigated extensively in hematopoiesis, the functional significance of other members of the 2-oxoglutarate (2-OG)-dependent protein hydroxylase family of enzymes remains poorly defined in HSC biology and multilineage hematopoiesis. Here, by using hematopoietic-specific conditional gene deletion, we reveal that the 2-OG–dependent protein hydroxylase JMJD6 is essential for short- and long-term maintenance of the HSC pool and multilineage hematopoiesis. Additionally, upon hematopoietic injury, Jmjd6-deficient HSCs display a striking failure to expand and regenerate the hematopoietic system. Moreover, HSCs lacking Jmjd6 lose multilineage reconstitution potential and self-renewal capacity upon serial transplantation. At the molecular level, we found that JMJD6 functions to repress multiple processes whose downregulation is essential for HSC integrity, including mitochondrial oxidative phosphorylation (OXPHOS), protein synthesis, p53 stabilization, cell cycle checkpoint progression, and mTORC1 signaling. Indeed, Jmjd6-deficient primitive hematopoietic cells display elevated basal and maximal mitochondrial respiration rates and increased reactive oxygen species (ROS), prerequisites for HSC failure. Notably, an antioxidant, N-acetyl-l-cysteine, rescued HSC and lymphoid progenitor cell depletion, indicating a causal impact of OXPHOS-mediated ROS generation upon Jmjd6 deletion. Thus, JMJD6 promotes HSC maintenance and multilineage differentiation potential by suppressing fundamental pathways whose activation is detrimental for HSC function.

Quantitative analysis of redox proteome reveals oxidation-sensitive protein thiols acting in fundamental processes of developmental hematopoiesis

“…5 d). Among these proteins Jmjd6, Pik3ap1 and Samsn1 play a role in the regulation of B lymphopoiesis, including B cell differentiation, activation and B cell receptor signaling [ [52] , [53] , [54] ]. To test the functional effect of the Denr-Mcts1 complex in fetal HSPCs, we used CRISPR-Cas9 to delete Denr ( Fig.…”

Jmjd6 regulates ES cell homeostasis and enhances reprogramming efficiency

“…Since histone arginine methylations are generally associated with transcriptional activation [ 27 , 28 , 29 , 30 ]. Indeed, JMJD6 promotes self-renewal of hematopoietic stem cells and adipose-derived mesenchymal stem cells [ 31 , 32 ]. Interestingly, Jmjd6 may regulates gene expression by integrating with chromatin [ 33 ].…”

Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis

“…CFC assays were carried out using MethoCult TM M3434 (STEMCELL Technologies) methylcellulose medium ( Lawson et al, 2021a , b ). Two technical replicates were used per each biological replicate in each experiment.…”