Demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are among the most devastating and disabling disorders, leading to severe handicap and even death. A common feature of demyelinated lesions is the differentiation block of oligodendrocyte precursors (OPC) at a premyelinating stage. However, at present, the mechanistic basis for failure of proper myelin repair is not fully understood. Understanding the molecular control of myelination and remyelination is crucial for treating demyelinating diseases. A large body of work has shown that chromatin-remodeling events govern the transcriptional and epigenetic establishment of the cellular differentiation program. Chromatin remodeling enzymes including histone modifying enzymes and ATP-dependent chromatin remodelers modulate local chromatin structure and facilitate recruitment of essential factors required for gene expression. Recently we demonstrated the histone deacetylases HDAC1/2 are essential for oligodendrocyte myelination. In a search of HDAC1/2-interacting proteins, we identified Brg1 (Brahma-related gene-1), the central catalytic subunit of SWI/SNF-like chromatin-modifying enzymatic complex, which was found associated with HDAC1/2 in oligodendrocytes. Deletion of Brg1 in the oligodendrocyte lineage resulted in severe myelination deficits, suggesting that Brg1 is critical for the control of CNS myelination. I addition, in a search of Brg1 downstream genes we identified an oligodendrocyte-enriched ATP dependent chromatin-remodeler Chd7, mutations of which causes CHARGE syndrome with severe neurological disorders. The goal of this proposal is to gain a better insight into the molecular basis of the myelination process regulated by Brg1 and its downstream genes. We will utilize conditional in vivo mutagenesis approaches to define the role of Brg1 in CNS myelination and myelin repair in a spatiotemporally controlled manner. In addition, a genome-wide target gene screen will be used to identify Brg1-regulated genes that control myelination. The long-term objective of the research proposed here is to develop compounds that modulate the activity of Brg1 complexes and its downstream effectors to promote myelination and remyelination. The proposed studies will not only advance our understanding of the mechanisms of CNS myelination, but also identify potential targets for treating patients with demyelinating diseases such as MS, leukodystrophies, stroke, spinal cord and brain injury.

Public Health Relevance

The studies proposed in research plans will provide a better understanding of molecular control of CNS myelination and remyelination. They will not only have scientific merits but also could offer new strategies in treating patients with demyelinating neurological disorders such as multiple sclerosis, periventricular cerebral palsy, the common cause of severe disability in infants, stroke and spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075243-05
Application #
8842209
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
$341,250
Indirect Cost
$122,500
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Lu, Xu-Feng; Cao, Xiao-Yue; Zhu, Yong-Jie et al. (2018) Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway. Cell Death Dis 9:398
He, Xuelian; Zhang, Liguo; Queme, Luis F et al. (2018) A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration. Nat Med 24:338-351
Zuo, Hao; Wood, William M; Sherafat, Amin et al. (2018) Age-Dependent Decline in Fate Switch from NG2 Cells to Astrocytes After Olig2 Deletion. J Neurosci 38:2359-2371
Jiang, Minqing; Rao, Rohit; Wang, Jincheng et al. (2018) The TSC1-mTOR-PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage-specific manner. Glia 66:1947-1959
Wu, Lai Man Natalie; Deng, Yaqi; Wang, Jincheng et al. (2018) Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. Cancer Cell 33:292-308.e7
Merten, Nicole; Fischer, Julia; Simon, Katharina et al. (2018) Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation. Cell Chem Biol 25:775-786.e5
Gregath, Alexander; Lu, Qing Richard (2018) Epigenetic modifications-insight into oligodendrocyte lineage progression, regeneration, and disease. FEBS Lett 592:1063-1078
Marie, Corentine; Clavairoly, Adrien; Frah, Magali et al. (2018) Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8. Proc Natl Acad Sci U S A 115:E8246-E8255
Moyano, Ana Lis; Steplowski, Jeffrey; Wang, Haibo et al. (2018) microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease. Mol Ther 26:730-743
He, Li; Yu, Kun; Lu, Fanghui et al. (2018) Transcriptional Regulator ZEB2 Is Essential for Bergmann Glia Development. J Neurosci 38:1575-1587

Showing the most recent 10 out of 46 publications