Project description:Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 expression, and functions as a molecular switch for oligodendrocyte and astrocyte lineage determination. Our data suggest that Hdac3 cooperates with p300 to prime and maintain oligodendrogenic programs while inhibiting Stat3-mediated astrogliogenesis, and thereby regulate phenotypic commitment at the point of oligodendrocyte-astrocytic fate decision. Examination of Hdac3 and p300 genomewide occupancy in differentiating oligodendrocytes
Project description:Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 expression, and functions as a molecular switch for oligodendrocyte and astrocyte lineage determination. Our data suggest that Hdac3 cooperates with p300 to prime and maintain oligodendrogenic programs while inhibiting Stat3-mediated astrogliogenesis, and thereby regulate phenotypic commitment at the point of oligodendrocyte-astrocytic fate decision. Gene expression profiling of optic nerve from P12 control and Hdac3 cKO mice
Project description:Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 expression, and functions as a molecular switch for oligodendrocyte and astrocyte lineage determination. Our data suggest that Hdac3 cooperates with p300 to prime and maintain oligodendrogenic programs while inhibiting Stat3-mediated astrogliogenesis, and thereby regulate phenotypic commitment at the point of oligodendrocyte-astrocytic fate decision.
Project description:Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 expression, and functions as a molecular switch for oligodendrocyte and astrocyte lineage determination. Our data suggest that Hdac3 cooperates with p300 to prime and maintain oligodendrogenic programs while inhibiting Stat3-mediated astrogliogenesis, and thereby regulate phenotypic commitment at the point of oligodendrocyte-astrocytic fate decision.
Project description:Schwann cell remyelination defects impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms that mediate remyelination block remain elusive. Upon small-molecule epigenetic screening, we identified HDAC3, a histone-modifying enzyme, as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 markedly enhances myelin growth and regeneration, and improves functional recovery after peripheral nerve injury. HDAC3 antagonizes myelinogenic neuregulin/PI3K/AKT signaling axis. Moreover, genome-wide profiling analyses reveal that HDAC3 represses pro-myelinating programs through epigenetic silencing, while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann-cell-specific deletion of either Hdac3 or Tead4 results in a profound increase in myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.
Project description:Schwann cell remyelination defects impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms that mediate remyelination block remain elusive. Upon small-molecule epigenetic screening, we identified HDAC3, a histone-modifying enzyme, as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 markedly enhances myelin growth and regeneration, and improves functional recovery after peripheral nerve injury. HDAC3 antagonizes myelinogenic neuregulin/PI3K/AKT signaling axis. Moreover, genome-wide profiling analyses reveal that HDAC3 represses pro-myelinating programs through epigenetic silencing, while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann-cell-specific deletion of either Hdac3 or Tead4 results in a profound increase in myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.
Project description:Astrocytes within specific brain regions contribute uniquely to regional circuits for higher-order brain function through interactions with local neurons. The regional diversification of astrocytes is dictated by their embryonic origin, yet the mechanisms governing their regional allocation remain unknown. Here we show that allocation of astrocytes to specific brain regions requires the transcription factor 4 (Tcf4) mediated fate restriction during brain development. Loss of Tcf4 in ventral telencephalic neural progenitors alters the fate of oligodendrocyte precursors to transient intermediate astrocyte precursor cells, resulting in mislocated astrocytes in the dorsal neocortex. These ectopic astrocytes originated from the ventral telencephalon engage with neurons and acquire features reminiscent of local neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during differentiation of oligodendrocyte precursors, thereby restricting the fate to oligodendrocyte lineage. Our study reveals that fate restriction governs regional astrocyte allocation, contributing to astrocyte diversification across brain regions.
Project description:p300 is a histone acetyltransferase that associates with crucial biological processes. p300 acetylates all four histones in the nucleosome, a basic unit of chromatin, and alters chromatin structure and dynamics. In this study, we performed structural and biochemical analysis to understand the nucleosome binding by p300. Crosslinking mass spectrometry suggests that the p300 catalytic core binds to nucleosomes in multiple binding forms to acetylate different histone tails.