Human positive coactivator 4 controls heterochromatinization and silencing of neural gene expression by interacting with REST/NRSF and CoREST.
The highly abundant, multifunctional transcriptional positive coactivator 4 (PC4) plays important roles in transcription, replication and DNA repair. Our recent work showed that PC4 is a bona fide non-histone component of chromatin. Here, we report that knockdown of PC4 dramatically alters heterochromatin organization of the genome, accompanied by increased H3K9 (histone H3 at lysine residue 9)/14 acetylation, H3K4 trimethylation and reduction in the level of H3K9 dimethylation. These posttranslational modifications of histone H3 result in overexpression of normally silenced genes (e.g., neural genes) located in heterochromatin. The results of ChIP (chromatin immunoprecipitation) and re-ChIP assays showed that overexpression of a neuronal-specific gene is accompanied by histone hyperacetylation. We further show that PC4 interacts with heterochromatin protein 1alpha, REST/NRSF (RE1-silencing transcription factor/neuron-restrictive silencer factor) and CoREST to establish the repressed state of neural genes in nonneuronal cells. Thus, PC4 plays a crucial role in maintaining a dynamic chromatin state and heterochromatin gene silencing.
Das
Chandrima
C
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur PO, Bangalore 560064, India.
Gadad
Shrikanth S
SS
Kundu
Tapas K
TK
D000107:Acetylation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism* / Q000648:ultrastructure; D006657:Histones / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D006657:Histones; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D015222:Sodium Channels; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C121019:RCOR1 protein, human; C568251:SCN2A protein, human; C509201:SUB1 protein, human