Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells

By Daniel A. Lim, Yin-Cheng Huang, T. Swigut, Anika L. Mirick, Jose Manuel García-Verdugo, J. Wysocka, P. Ernst, Arturo Alvarez-Buylla. 2009

390 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Developmental Neuroscience, Molecular Biology

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Citations in the corpus

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions (2011, background): “Among many histone modifiers, Mll1 (mixed-lineage leukemia 1), a TrxG member that encodes an H3K4methyltransferase, is specifically required for neuronal differentiation in the adult SVZ, at least partially through its direct target Dlx2 (Lim et al., 2009).”
FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis (2009, methodology): “…a particular hGFAP-Cre transgenic line that has been well documented in multiple published studies to be highly active in neural stem/ progenitor cells (Figures S1G and S1H; Zheng et al., 2008; Zhuo et al., 2001; Lim et al., 2009) although it is also active in developing and mature astrocytes.”
In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. (2010, background): “, 2004, 2005) or the chromatin remodeling factor Mll that is involved in the upregulation of the Dlx family of transcription factors (Lim et al., 2009).”
Epigenetic regulation of neurogenesis in the adult mammalian brain (2011, background): “In another example, mixed-lineage leukaemia 1 (Mll1), a TrxG member that encodes an H3K4 methyltransferase, is specifically required for neuronal differentiation, but not glial differentiation, from SVZ neural progenitors (Lim et al., 2009).”
Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. (2011, positive): “Recent work has highlighted the essential role of epigenetic regulators such as the chromatin-modifying protein Mll1 and the microRNA miR-124 in the control of neurogenesis (Lim et al., 2006; Cheng et al., 2009; Lim et al., 2009) (reviewed in Hwang, Alvarez-Buylla, and Lim, in press).”