Monoallele deletion of CBP leads to pericentromeric heterochromatin condensation through ESET expression and histone H3 (K9) methylation

Abstract

Chromatin remodeling is tightly controlled under physiological conditions. Alterations in chromatin structure are involved in the pathogenesis of neuronal systems. We found that the monoallelic deletion of CREB binding protein (CBP) results in the induction of ERG-associated protein with SET domain (ESET) and increases trimethylation of histone H3 (K9) and condensation of pericentromeric heterochromatin structure in neurons. Nested deletion and mutational analysis of the ESET promoter further demonstrated that the Ets-2 transcription factor regulates transcriptional activity of the ESET gene. In CBP+/- mice, Ets-2 occupancy in the ESET promoter DNA was markedly elevated. Our results suggest that CBP is a transcriptional repressor of ESET gene expression by limiting Ets-2 transcriptional activity, while CBP siRNA enhances basal and Ets-2-dependent ESET transcriptional activity. Altered expression of the ESET gene and hypertrimethylation of H3 (K9) correlate with striatal neuron atrophy and dysfunction in CBP+/- mice. These results establish an alternative pathway that loss of CBP leads to the pericentric heterochromatin condensation through ESET expression and trimethylation of H3 (K9).

CLLD8/KMT1F Is a Lysine Methyltransferase That Is Important for Chromosome Segregation

“…Indeed, SETDB1/KMT1E, which is mainly involved in the regulation of euchromatic sequence and associates with corepressors at silenced promoters (29), was also found to modulate H3K9 trimethylation at pericentric heterochromatin and to interact with HP1 (30,31), suggesting that it may also contribute to heterochromatin formation. Thus, the mechanism by which KMT1F modulates histone methylation is currently unknown, but despite the fact that SUV39H, G9a, and KMT1F modify the same residue, they may also play unique roles in the distribution of H3K9me3 and/or involve different protein complexes or noncoding RNAs (28,31).…”

Implication of Epigenetic Modifications in Neurodegenerative Disorders: Traces and Imprints

“…The genetic components responsible for their development have already been discussed above. Clinical studies aimed at treatment of Alzheimer's have affirmed a possible approach wherein in vitro or dietary administration of the components required for production of SAM like folate, homocysteine and B -group vitamins can be utilized to restore methylation levels of PSEN1, protract brain atrophy and minimize oxidative stress (Figure 3) [76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94]. In addition, several HDAC inhibitors have been developed for the therapeutic strategies targeted for Alzheimer's.…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…Because abnormally increased histone methylation occurs concurrently with altered histone acetylation related to CBP dysfunction, our group hypothesized that CBP may have effects independent of HAT activity that contribute to chromatin remodeling [68]. We discovered an alternative mechanism of histone methylation associated with mono-allelic deletion of CBP that is regulated independently from HAT activity by induction of erythroblast transformation-specific (ETS)-related gene (ERG)-associated protein with Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins (SET) domain [68].…”

“…We discovered an alternative mechanism of histone methylation associated with mono-allelic deletion of CBP that is regulated independently from HAT activity by induction of erythroblast transformation-specific (ETS)-related gene (ERG)-associated protein with Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins (SET) domain [68]. We hypothesized that CBP represses the expression of SETDB1 gene and maintains an appropriate level of trimethylated histone H3K9 (H3K9me3) in neurons.…”

“…Altered expression of HMT and elevated H3K9me3 are linked to upstream transcriptional deregulation in both animal models of HD and in HD patients [65,66,70]. Thus, the increase of H3K9me3 level has been correlated with the formation of large constitutive heterochromatin domains and is thought to promote gene silencing in both global and local repression of transcription, including CHRM1 [68,71]. We recently discovered a novel epigenetic pathway whereby H3K9me3-dependent heterochromatin condensation leads to transcriptional deregulation of muscarinic acetylcholine (Ach) receptor 1 (CHRM1) by occupying its promoter in HD striatal cells [69].…”