Publication Date:
2009-02-13
Description:
Epigenetic mechanisms that maintain neurogenesis throughout adult life remain poorly understood. Trithorax group (trxG) and Polycomb group (PcG) gene products are part of an evolutionarily conserved chromatin remodelling system that activate or silence gene expression, respectively. Although PcG member Bmi1 has been shown to be required for postnatal neural stem cell self-renewal, the role of trxG genes remains unknown. Here we show that the trxG member Mll1 (mixed-lineage leukaemia 1) is required for neurogenesis in the mouse postnatal brain. Mll1-deficient subventricular zone neural stem cells survive, proliferate and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. In Mll1-deficient cells, early proneural Mash1 (also known as Ascl1) and gliogenic Olig2 expression are preserved, but Dlx2, a key downstream regulator of subventricular zone neurogenesis, is not expressed. Overexpression of Dlx2 can rescue neurogenesis in Mll1-deficient cells. Chromatin immunoprecipitation demonstrates that Dlx2 is a direct target of MLL in subventricular zone cells. In differentiating wild-type subventricular zone cells, Mash1, Olig2 and Dlx2 loci have high levels of histone 3 trimethylated at lysine 4 (H3K4me3), consistent with their transcription. In contrast, in Mll1-deficient subventricular zone cells, chromatin at Dlx2 is bivalently marked by both H3K4me3 and histone 3 trimethylated at lysine 27 (H3K27me3), and the Dlx2 gene fails to properly activate. These data support a model in which Mll1 is required to resolve key silenced bivalent loci in postnatal neural precursors to the actively transcribed state for the induction of neurogenesis, but not for gliogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800116/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800116/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lim, Daniel A -- Huang, Yin-Cheng -- Swigut, Tomek -- Mirick, Anika L -- Garcia-Verdugo, Jose Manuel -- Wysocka, Joanna -- Ernst, Patricia -- Alvarez-Buylla, Arturo -- 5R37-NS028478/NS/NINDS NIH HHS/ -- R37 NS028478/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):529-33. doi: 10.1038/nature07726. Epub 2009 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Street M779, San Francisco, California 94143, USA. limd@neurosurg.ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19212323" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Animals, Newborn
;
Basic Helix-Loop-Helix Transcription Factors/metabolism
;
Cell Differentiation
;
Cell Lineage
;
Cell Proliferation
;
Cell Survival
;
Cells, Cultured
;
Chromatin/*metabolism
;
*Chromatin Assembly and Disassembly
;
Chromatin Immunoprecipitation
;
Histone-Lysine N-Methyltransferase
;
Histones/metabolism
;
Homeodomain Proteins/chemistry/genetics/metabolism
;
Methylation
;
Mice
;
Myeloid-Lymphoid Leukemia Protein/deficiency/genetics/*metabolism
;
Nerve Tissue Proteins/metabolism
;
*Neurogenesis
;
Neuroglia/cytology/metabolism
;
Neurons/*cytology/metabolism
;
Olfactory Bulb/cytology/metabolism
;
Stem Cells/*cytology/metabolism
;
Transcription Factors/chemistry/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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