Poot, R. A. | Search bioRxiv

bioRxiv2024

The Integrator complex prevents premature neuronal differentiation through global control of transcription elongation.

Transcription pause-release constitutes a key step in the regulation of gene expression. Pathogenic variants in various pausing regulators have been identified in neurodevelopmental disorders, but how transcription pause-release regulates neural development remains largely unknown. Here we show that a patient-specific in-frame deletion in Integrator subunit 8 (INTS8) that prevents association of this subunit with the Integrator complex results in a global increase in nascent transcription and precocious expression of neuronal genes in progenitor cells. Consequently, differentiating neural progenitors fail to sustain a proliferating progenitor cell population during cortical neuronal network formation, resulting in network collapse. We show that attenuation of RNApol2 pause-release by targeted degradation of BRD4 can revert neuronal gene activation and prevent premature progenitor cell loss. Our data demonstrate that a fine-tuned balance between RNApol2 pausing and elongation is crucial for normal neuronal development and suggest transcription pause-release as a druggable target for neurological defects in developmental disorders.

developmental biology↗

bioRxiv2020

Genetic variants for head size share genes and pathways with cancer

The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants - such as TP53, PTEN and APC - were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.

genomics↗