luteolin More recently the JmjC domain histone H K di demeth
More recently, the JmjC domain histone H3K36 di-demethylase KDM2B/FBXL10 has also been shown to play an important role in definitive hematopoiesis . Kdm2b is highly expressed in the HE, and its deletion (Tie2) caused embryonic lethality due to a precipitous drop in the number of hemogenic endothelial luteolin within the AGM. Conversely, Vav1;Kdm2b mice were viable, but displayed a dramatic reduction in the number of long-term HSCs and defective lymphopoiesis, which was accompanied by a concomitant upregulation of myeloid differentiation . A similar phenotype was also observed in Mx1;Kdm2b mice upon pIpC administration, suggesting an important role for Kdm2b in the maintenance of HSPCs and the regulation of lymphopoiesis, the latter in a JmjC domain–dependent manner . Gene expression and chromatin immunoprecipitation studies coupled with next-generation sequencing showed that KDM2B associates, in a mutually exclusive manner, with Trithorax (TrxG)-active and Polycomb (PcG)-repressed chromatin to regulate quiescence, cell fate, and lineage commitment. In mammalian cells, the TrxG proteins MLL1–4 reside in a complex that includes WDR5, RBBP5, ASH2L, and DPY30. This complex methylates histone H3K4 to activate transcription. Although it does not interact physically, KDM2B co-binds with TrxG proteins on gene promoters to enhance NOTCH1 signaling and promote T-cell commitment. Conversely, PcG proteins reside in two complexes, Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2), which function as global transcriptional repressors through H2AK119 ubiquitination and H3K27 trimethylation, respectively. KDM2B is an integral component of a noncanonical PRC1 and cross-talks with PRC2 to repress transcriptional programs of myeloid differentiation. Therefore, these distinct functions of KDM2B ensure the faithful execution of transcriptional programs for the initiation of lymphoid and the repression of myeloid commitment .
Hematopoietic cell migration is critical for normal hematopoiesis 9, 10. KDM6A/UTX, an H3K27me3 demethylase encoded by the X chromosome, has been shown to play an important role in the migration of HSCs in response to SDF-1/CXCR4 signaling, although the exact molecular mechanism(s) remains elusive . Female Kdm6a-null mice displayed hematopoietic phenotypes, such as myelodysplasia and suppressed erythro-megakaryocytopoiesis, whereas their male counterparts showed no phenotype. Given that UTY, encoded by the Y chromosome and exhibiting >80% similarity to KDM6A, does not demethylate H3K27me3 due to mutations in the JmjC domain 19, 20, this suggests that KDM6A regulates these responses in a demethylase-independent manner. KDM6A is an integral component of MLL3/4 H3K4 methyltransferase complexes 21, 22 and likely functions as a scaffold to facilitate the recruitment or the activity of this complex toward its substrate. Interestingly, although KDM6A demethylase activity is dispensable in definitive hematopoiesis, H3K27me3 demethylation by either KDM6A or KDM6B/JMJD3 (encoded by an autosomal gene) is crucial for the terminal steps of T-cell differentiation . Another study showed that T-cell–specific ablation of KDM6B promoted Th2 and Th17 and inhibited Th1 and Treg differentiation under different cytokine-induced conditions . The latter was also dependent on active demethylation and changes in the expression of key genes such as Tbx21, Gata3, and Foxp3. The preferential impact of KDM6A/B on late T-cell maturation may be linked to the enzymes’ role in integrating extracellular cues and cytokine signals to regulate differentiation 23, 24. Further studies using Cre strains at different stages of hematopoietic development and the generation of demethylation-deficient mutants of KDM6A and KDM6B through CRISPR-mediated genome editing will be useful in determining the demethylase-dependent and -independent functions of these enzymes in hematopoiesis.
Histone demethylases in hematopoietic malignancies