Systematic Analysis of SIN3 Histone Modifying Complex Components During Development

Abstract

Establishment and maintenance of histone acetylation levels are critical for metazoan development and viability. Disruption of the balance between acetylation and deacetylation by treatment with chemical histone deacetylase (HDAC) inhibitors results in loss of cell proliferation, differentiation and/or apoptosis. Histone deacetylation by the SIN3 complex is essential in Drosophila and mice, as loss of the scaffolding factor SIN3 or the associated HDAC results in lethality. The objective of this study is to elucidate contributions of SIN3 complex components to these essential processes. We used the Drosophila model organism to carry out a systematic functional analysis of the SIN3 complex. We find that SIN3 associated proteins are essential for viability and cell proliferation during development. Additionally, tissue specific reduction of SIN3 complex components results in abnormal wing development. Interestingly, while knockdown of each factor resulted in similar phenotypes, their individual effects on recruitment of SIN3 to polytene chromosomes are distinct. Reduction of some factors leads to large changes in the morphology of the chromosome and/or greatly reduced SIN3 binding. These findings suggest that while individual SIN3 complex components work through distinct molecular mechanisms, they each make a substantial contribution to the overall function of this highly conserved histone deacetylase complex.

SIN3 acts in distinct complexes to regulate the germline transcriptional program inC. elegans

“…Interestingly simultaneous inactivation of SIN3S and SIN3L complex subunits in both athp-1;suds-3 and athp-1;hda-3 double mutant animals resulted in fully penetrant sterility (Figure 2C), suggesting redundant functions in the maintenance of germline function. Alternatively, or in addition, athp-1 , hda-3 and suds-3 may play redundant, sin-3 independent functions required for fertility (Barnes et al, 2018).…”

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

“…Histone demethylase KDM5B, which is part of the PF1 complex, inhibits genes involved in inflammatory response, cell proliferation and cell adhesion in MDA-MB-231 cell line [ 40 , 41 ]. We previously reported that disrupting the interaction of KDM5B with SIN3A results in decrease in H3K4me3 signal and enhances binding of KDM5B to the promoter of ITGA6 gene [11] .…”

Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex

“…Depletion of SIN3A causes loss of proliferative potential 21–23 and depletion of SIN3B inhibits the ability of proliferating cells to exit the cell cycle 21,24–26 . Because of the ability of SIN3 complexes to regulate cell differentiation 4–6 and proliferation in cancer cells, they are drug targets 27–30 . Consequently, several inhibitors have been developed and used in clinical trials 31,32 , however success on this has been limited by the lack of specificity of these compounds towards the distinct HDAC1/2 complexes 33 .…”

“…Class I HDACs (HDAC1/2/3/8) represent the principle nuclear deacetylases that regulate transcription. HDAC1 and HDAC2 (HDAC1/2) are essential for cellular differentiation, development [4][5][6][7] and function as part of multi-subunit complexes 8 . HDAC1/2 are Zn 2+ -dependent enzymes which catalyse the nucleophilic attack of a Zn 2+bound water molecule to a Zn 2+ -polarized N-ε-acetyl-lysine side-chain carbonyl.…”

“…Depletion of SIN3A causes loss of proliferative potential [21][22][23] and depletion of SIN3B inhibits the ability of proliferating cells to exit the cell cycle 21,[24][25][26] . Because of the ability of SIN3 complexes to regulate cell differentiation [4][5][6] and proliferation in cancer cells, they are drug targets [27][28][29][30] .…”