Intellectual Disability and Brain Development: Role of Epigenetic Regulators
Research in Dr. Picketts’ laboratory focuses on the role of chromatin remodeling proteins in neural development and intellectual disability disorders. We utilize transgenic mouse models in which genes encoding epigenetic regulators are genetically inactivated to identify their requirement during brain development and to obtain insight into the mechanisms causing intellectual disability. Determining the genes and developmental pathways regulated by these epigenetic regulators is critical for the generation of novel therapeutics for patients.
1. Defining the molecular role of ATRX
The involvement of chromatin remodeling proteins in human disease was established by our cloning of the ATRX gene as the cause of a severe X-linked intellectual disability (XLID) syndrome usually associated with alpha-thalassemia. Recent excitement in the field came from the findings that ATRX in combination with DAXX loads the histone variant H3.3 onto telomeres and that ATRX recognizes G-quadruplex structures. Our most recent work (Huh et al (2012) J. Clin. Invest. 122:4412-23) involved ATRX ablation in muscle. These mice have a regeneration deficit from an inability to activate satellite cell expansion that arises from stalled replication and telomere fragility. We are currently investigating the role of ATRX in the resolution of G-quadruplexes, since the structures are prevalent at telomeres.
2. Mammalian ISWI proteins in brain development
The ISWI proteins, SNF2H and SNF2L have complementary expression patterns in the developing mouse brain. Snf2h is highly expressed in progenitors whereas Snf2l expression becomes more prevalent upon neuronal differentiation. We have generated Snf2h and Snf2l mutant mice to investigate the role of these proteins in brain development. The loss of Snf2l results in mice with a larger brain due to increased proliferation of intermediate progenitor cells. In contrast, Snf2h cKO mice have a hypoplastic cerebellum due to poor proliferation of granule neuron progenitors. The expansion and differentiation of these progenitors is controlled by homeotic transcription factors, namely Foxg1 in the forebrain and En-1 in the cerebellum. We are currently investigating the coordinate regulation of these genes by the ISWI proteins with the hypothesis that Snf2h is required for their activation to promote proliferation while Snf2l promotes their repression leading to differentiation.
3. Mutations in PHF6 as the cause of Borjeson-Forssman-Lehmann (BFLS) syndrome and T-ALL
BFLS is an XLID caused by mutations in the PHF6 gene. Somatic mutations in PHF6 result in T cell acute lymphoblastic leukemia (T-ALL). PHF6 has two PHD domains suggesting that it regulates chromatin. The protein is localized in both the nucleus and the nucleolus. We have utilized a proteomics approach to identify OHF6-interacting proteins to determine its function. We identified that PHF6 interacts with the NURD remodeling complex in the nucleus and are currently using ChIP-Seq to define the target genes that should provide insight into why mutations cause both XLID and T-ALL. Current work has focused on its role in the nucleolus, where it appears to regulate the expression of the rDNA genes.
Gibbons, RJ, Picketts, DJ, and Higgs, DR. (1995) X-linked mental retardation associated with a thalassaemia (ATR-X syndrome) results from mutations in a putative global transcriptional regulator. Cell 80, 837-845.
Barak, O., Lazzaro, MA., Lane, WS., Speicher DW., Picketts, DJ., Shiekhattar R. Isolation of human NURF: a regulator of Engrailed gene expression. EMBO J. (2003) 22:6089-6100.
Bérubé, NG, Jagla M, Vanderluit, JL, Garrick, D, Gibbons, RJ, Higgs, DR, Slack, RS, and Picketts, DJ. The chromatin remodeling protein ATRX is critical for neuronal survival during corticogenesis. (2005) J. Clin. Invest. 115: 258-267. Impact Factor: 15.754
Yip, DJ, Corcoran, CP, DeMaria, A, Rennick, S, Rudnicki, MA, Messier, C, and Picketts DJ. Snf2l regulates Foxg1-dependent progenitor cell expansion in the developing brain. (2012) Dev Cell. 2012 Apr 17;22(4):871-8. Impact Factor: 14.030
Alvarez-Saavedra, M., Lagali, P., Yan, K., Mears, A., De Repentigny,
Y., Hashem, E., Wallace, V.A., Kothary, R., Stopka, T., Skoultchi,
A.I., and Picketts, D.J. Snf2h mediates histone dynamics to control
cerebellar development and function. Nature Comm (2014) 5:4181