Epigenetic Regulation in Brain Development and Disease Pathology
Disease gene identification for neurodevelopmental disorders has demonstrated that a large number encode epigenetic regulators. Amongst these are the ATP-dependent chromatin remodeling proteins that utilize the energy from ATP-hydrolysis to remove, remodel, or replace nucleosomes. Research in Dr. Picketts’ laboratory primarily focuses on understanding how aberrant chromatin remodeling affects brain development, cognition, and brain repair. Determining the genes and developmental pathways affected by these aberrant chromatin remodelers is critical to understanding human disease and for the generation of novel therapeutics.
Ongoing Projects:
1. Defining ATRX functions in neural development
We generated the first mouse models of the ATR-X syndrome and demonstrated a role for ATRX in mediating replication stress in the dividing progenitor cell population. We continue to investigate ATRX interacting proteins involved in mediating replication stress using both in vitro and in vivo model systems. A prominent unanswered question is what does ATRX do in a post-mitotic neuron? To address this question, we study the role of ATRX in the retina where it has importance cell non-autonomous roles and in a novel mouse model that presents with prominent features observed in human patients. Current projects with these animal models should highlight the molecular mechanisms underlying neuronal functions and learning deficits.
2. Mammalian ISWI proteins as mediators of brain size
The ISWI proteins, SNF2H and SNF2L co-regulate the expression of key neural developmental TFs (eg. Foxg1, En1) to regulate brain size. Snf2h ablation promotes progenitor differentiation while Snf2l loss enhances progenitor expansion to increase neuronal output. While this was thought to result from the actions of Snf2h- or Snf2l-specific complexes, recent studies have indicated that Snf2h and Snf2l are interchangeable. As such, differences in intrinsic remodeling activity of Snf2h versus Snf2l, and/or the temporal expression of different complexes may be key determinants. Current projects focus on characterizing the roles of individual complexes (eg. NuRF) through the analysis of partner proteins, and on genomic studies to define the co-regulated genes and remodeling alterations that drive the balance between proliferation and differentiation.
3. Mutations in PHF6 cause the Borjeson-Forssman-Lehmann (BFLS) syndrome
BFLS is caused by mutations in the PHF6 gene. PHF6 has two PHD domains and localizes to both the nucleus and the nucleolus. We have shown that it interacts with the NURD remodeling complex within the nucleus and regulates rDNA expression with the nucleolus. We have recently generated transgenic mice harboring the common human mutation (p.R342X) which will help us delineate its role in neocortical development and cognition.
4. VGF Neuropeptides as Mediators of Neuronal Damage
We identified VGF as an upregulated gene in exercising Snf2h conditional knockout mice. The upregulation of VGF promoted the survival of these animals, in part, by stimulating the clearance of cellular debris and the remyelination of neuronal axons. This work indicated that VGF should be examined as a potential therapeutic to promote brain recovery. Ongoing projects are exploring the role of VGF in promoting stroke recovery and for enhancing remyelination in models of Multiple Sclerosis.
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.
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.
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
Alvarez-Saavedra M., De Repentigny Y., Yang D., O'Meara R., Yan K., Racacho L., Ioshikhes I., Parks RJ., Kothary R., Picketts, D.J. (2016) Voluntary Running Triggers VGF-Mediated Oligodendrogenesis to Prolong the Lifespan of Snf2h-Null Ataxic Mice. Cell Rep. 17: 862-875
