RNA polymerase II (RNAPII) controls expression of all protein-coding genes and most noncoding loci in higher eukaryotes. Calibrating RNAPII activity requires an assortment of polymerase-associated factors that are recruited at sites of active transcription. The Integrator complex is one of the most elusive transcriptional regulators in metazoans, deemed to be recruited after initiation to help establish and modulate paused RNAPII.
View Article and Find Full Text PDFNat Rev Mol Cell Biol
March 2023
In higher eukaryotes, fine-tuned activation of protein-coding genes and many non-coding RNAs pivots around the regulated activity of RNA polymerase II (Pol II). The Integrator complex is the only Pol II-associated large multiprotein complex that is metazoan specific, and has therefore been understudied for years. Integrator comprises at least 14 subunits, which are grouped into distinct functional modules.
View Article and Find Full Text PDFSubunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features.
View Article and Find Full Text PDFIn a 2003 study, we examined five antecedents of school shootings - a history of rejection, acute rejection experience, history of psychological problems, fascination with death or violence, and fascination with guns. In three studies, the current project examined the role of these factors in 57 K-12 shootings, 24 college/university shootings, and 77 mass shootings that occurred since the original study. Over half of all shooters had a history of psychological problems.
View Article and Find Full Text PDFGene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6.
View Article and Find Full Text PDFThe control of cell fate is an epigenetic process initiated by transcription factors (TFs) that recognize DNA motifs and recruit activator complexes and transcriptional machineries to chromatin. Lineage specificity is thought to be provided solely by TF-motif pairing, while the recruited activators are passive. Here, we show that INTS13, a subunit of the Integrator complex, operates as monocytic/macrophagic differentiation factor.
View Article and Find Full Text PDFAT-rich interactive domain-containing proteins 1A and 1B (ARID1A and ARID1B) are mutually exclusive subunits of the chromatin remodeler SWI/SNF. ARID1A is the most frequently mutated chromatin regulator across all cancers, and ovarian clear cell carcinoma (OCCC) carries the highest prevalence of ARID1A mutations (∼57%). Despite evidence implicating ARID1A in tumorigenesis, the mechanism remains elusive.
View Article and Find Full Text PDFAim: DNA methylation is recognized by methyl-CpG-binding domain (MBD) proteins. Multiple MBDs are linked to neurodevelopmental disorders in humans and mice. However, the functions of MBD2 are poorly understood.
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