H3K27me3 regulates BMP activity in developing spinal cord.
During spinal cord development, the combination of secreted signaling proteins and transcription factors provides information for each neural type differentiation. Studies using embryonic stem cells show that trimethylation of lysine 27 of histone H3 (H3K27me3) contributes to repression of many genes key for neural development. However, it remains unclear how H3K27me3-mediated mechanisms control neurogenesis in developing spinal cord. Here, we demonstrate that H3K27me3 controls dorsal interneuron generation by regulation of BMP activity. Our study indicates that expression of Noggin, a BMP extracellular inhibitor, is repressed by H3K27me3. Moreover, we show that Noggin expression is induced by BMP pathway signaling, generating a negative-feedback regulatory loop. In response to BMP pathway activation, JMJD3 histone demethylase interacts with the Smad1/Smad4 complex to demethylate and activate the Noggin promoter. Together, our data reveal how the BMP signaling pathway restricts its own activity in developing spinal cord by modulating H3K27me3 levels at the Noggin promoter.
Akizu
Naiara
N
Department of Genomic Regulation, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Baldiri i Reixac 15-21, Parc Científic de Barcelona, Barcelona, Spain.
Estarás
Conchi
C
Guerrero
Laura
L
Martí
Elisa
E
Martínez-Balbás
Marian A
MA
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002642:Chick Embryo; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008959:Models, Neurological; D055495:Neurogenesis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D017931:DNA Primers; D006657:Histones; D012333:RNA, Messenger; D051785:Smad Proteins; D000099176:Noggin Protein