When eukaryotic cells enter mitosis, transcription is abruptly silenced. Earlier studies indicated that most transcription factors and RNA polymerase II (RNAP II) are displaced when chromatin is condensed into mitotic chromosomes. A more recent study suggested that hitherto unidentified factors might 'bookmark' previously active genes for rapid reactivation after cell division. Here we used chromatin immunoprecipitation (ChIP) assays to examine the association of TFIID, TFIIB, NC2 and RNAP II with various gene promoters in asynchronous and mitotic human cell populations. We show that TFIID and TFIIB can remain associated with active gene promoters during mitosis whereas RNA polymerase II is displaced, and also that NC2, originally identified as ubiquitous repressor of transcription, is associated with active gene promoters in asynchronous cell populations and is displaced from some, but not all, genes in mitotic cells. Consistent with the remarkable stability of TFIID-promoter complexes observed in vitro, our data suggest that these complexes can withstand condensation of chromatin into transcriptionally silent chromosomes. Stable TFIID-promoter complexes are therefore implicated in the propagation of cell-type-specific gene expression patterns through cell division.

Our study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ DSB repair and suggest that CHD1 loss may contribute to the genomic instability seen in this subset of PCas.

deletions and mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of-deleted/-mutated metastatic CRPC (mCRPC). We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses. CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic mutations, with six of these mutations not reported previously in prostate cancer. mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 = 0.001; CHD1: OR, 7.30, = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, = 0.002, CHD1: HR, 0.50, = 0.06). -mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment..

Transcriptional activation of the major histocompatibility complex (MHC) by IFNγ is a key step in cell-mediated immunity. At an early stage of IFNγ induction, chromatin carrying the entire MHC locus loops out from the chromosome 6 territory. We show here that JAK/STAT signalling triggers this higher-order chromatin remodelling and the entire MHC locus becomes decondensed prior to transcriptional activation of the classical HLA class II genes. A single point mutation of STAT1 that prevents phosphorylation is sufficient to abolish chromatin remodelling, thus establishing a direct link between the JAK/STAT signalling pathway and human chromatin architecture. The onset of chromatin remodelling corresponds with the binding of activated STAT1 and the chromatin remodelling enzyme BRG1 at specific sites within the MHC, and is followed by RNA-polymerase recruitment and histone hyperacetylation. We propose that the higher-order chromatin remodelling of the MHC locus is an essential step to generate a transcriptionally permissive chromatin environment for subsequent activation of classical HLA genes.