Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration

Abstract

The dynamic changes in chromatin conformation alter the organization and structure of the genome and further regulate gene transcription. Basically, the chromatin structure is controlled by reversible, enzyme-catalyzed covalent modifications to chromatin components and by noncovalent ATP-dependent modifications via chromatin remodeling complexes, including switch/sucrose nonfermentable (SWI/SNF), inositol-requiring 80 (INO80), imitation switch (ISWI) and chromodomain-helicase DNA-binding protein (CHD) complexes. Recent studies have shown that chromatin remodeling is essential in different stages of postnatal and adult neurogenesis. Chromatin deregulation, which leads to defects in epigenetic gene regulation and further pathological gene expression programs, often causes a wide range of pathologies. This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.

Exploring the role of transcriptional and post‐transcriptional processes in mRNA co‐expression

“…Experimentally this would be possible by perturbing specific kinetic steps of gene expression followed by single-cell transcriptomic and proteomic studies, that could provide interesting insights. [81][82][83][84] While small molecules with mRNA degradation inhibition functions are only just starting to be characterized, [85] transcript(s) specific perturbations (e.g., through the use of miRNA sponges [86] ) or inhibitors of nonsense-mediated mRNA decay [87,88] are already available. The implication of blocking transcript-shared mechanisms is perhaps a little less clear.…”

Chromatin remodeling enzyme Snf2h is essential for retinal cell proliferation and photoreceptor maintenance

“…The nucleosome is the basic structural unit of chromatin and is composed of four histone cores (H2A, H2B, H3 and H4) around which 147 bp of DNA are wrapped [1]. Various ATP-dependent chromatin remodeling complexes can reposition nucleosomes through the energy released by ATP hydrolysis [2,3]. Among the chromatin remodeling ATPases, the imitation switch (ISWI) family is highly conserved during evolution [4–7].…”

“…Snf2h is known to function as the catalytic ATPase in at least five distinct complexes in mammalian cells, including WICH, CHRAC, ACF, RSF and NoRC (reviewed in [3,15]). The presence of Snf2h within these complexes and the interactions of these complexes with other partners results in targeting of Snf2h for particular biological functions in chromatin.…”

Chromatin Remodeling Enzyme Snf2h Is Essential for Retinal Cell Proliferation and Photoreceptor Maintenance

“…The nucleosome is the basic structural unit of chromatin and is composed of four histone cores (H2A, H2B, H3, and H4) around which 147 bp of DNA are wrapped [ 1 ]. Various ATP-dependent chromatin remodeling complexes can reposition nucleosomes through the energy released via ATP hydrolysis [ 2 , 3 ]. Among the chromatin remodeling ATPases, the imitation switch (ISWI) family is highly conserved during evolution [ 4 , 5 , 6 , 7 ].…”

“…Snf2h is known to function as the catalytic ATPase in at least five distinct complexes in mammalian cells, including WICH, CHRAC, ACF, RSF, and NoRC (reviewed in [ 3 , 15 ]). The presence of Snf2h within these complexes and the interactions of these complexes with other partners result in the targeting of Snf2h for particular biological functions in chromatin.…”