Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program

Abstract

SUMMARYNeural development requires crosstalk between signaling pathways and chromatin. In this study, we demonstrate that neurogenesis is promoted by an interplay between the TGF pathway and the H3K27me3 histone demethylase (HDM) JMJD3. Genome-wide analysis showed that JMJD3 is targeted to gene promoters by Smad3 in neural stem cells (NSCs) and is essential to activate TGF-responsive genes. In vivo experiments in chick spinal cord revealed that the generation of neurons promoted by Smad3 is dependent on JMJD3 HDM activity. Overall, these findings indicate that JMJD3 function is required for the TGF developmental program to proceed.

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

“…These findings were similar, but not identical, to previous reports in chick, in which Smad3 is expressed in periventricular neuroepithelium but is relatively low in the pMN domain at the equivalent stage (Garcia-Campmany and Marti, 2007;Estaras et al, 2012). Compatible with previous findings, Smad2 was not detected (Garcia-Campmany and Marti, 2007).…”

“…Notably, the roles of this Smad2/3-activating cohort in oligodendrocyte development remain incompletely characterized. Complementary patterns of Tgfβ1-3 expression have been reported in embryonic mouse spinal cord (Flanders et al, 1991;Mecha et al, 2008), and Tgfβ1 has been shown to regulate Pdgf-driven proliferation of O-2A cells in vitro (McKinnon et al, 1993), while interactions between Olig2 and Smad3 have been linked to boundary determination of the pMN domain at HH stages 12-18 in chick neural tube (GarciaCampmany and Marti, 2007;Estaras et al, 2012). Studies have also reported expression of activin B (ActB) subunit and ActrIIb receptor mRNAs in developing mouse CNS at stages including those of OLP generation (Feijen et al, 1994).…”

“…Inhbb mRNA has been detected in mouse neural tube at similar time points (Feijen et al, 1994), although the longitudinal sections presented render comparison with our own results difficult. Interestingly, in situ hybridization studies in chick have also reported Smad3 mRNA within periventricular neuroepithelium, although the signal in the pMN domain was relatively low at HH stages 25-26 (E4.5-5.0, equivalent to mouse E13), and absent at stages 12-18 (E2.0-3.0, equivalent to mouse E10-11.5) (Garcia-Campmany and Marti, 2007;Estaras et al, 2012). In the chick, OLPs emerge from ventral neuroepithelium as in rodents, beginning at E6.0 (HH stages 28-29) (Ono et al, 1995).…”

Histone Methylation in the Nervous System: Functions and Dysfunctions

“…Consistent with this, JMJD3, an H3K27me3 demethylase, induces expression of neuronal genes such as Dlx5, Gad1/2, and Dcx [81]. Additionally, studies on embryonic stem cells also demonstrated that JMJD3 is required for commitment to the neuronal lineage [82] and activation of TGFbeta-responsive genes in neurons [83]. However, methylation of H3K27 by EZH2 in neural stem cells is required to maintain a proper balance between self-renewal of neural stem cells and differentiation into neurons and to prevent massive neurogenesis and depletion of the neural stem cell pool that would eventually result in a decreased number of neurons [7].…”

Histone Demethylase Jmjd3 Regulates Osteoblast Differentiation via Transcription Factors Runx2 and Osterix

“…Jmjd3 is regulated by a variety of differentiation cues and stress signals in macrophages (20), neuronal stem cells (21), and epidermal cells (22). In addition, Jmjd3-induced demethylation of H3K27me3 in the transcription start site of Nfatc1 gene plays a critical role in osteoclast differentiation (23).…”