Biology subjects

Grand, R. S.

Publications and source records attributed to Grand, R. S..

3 recordsLinked to original sources

bioRxiv2026

Essential genes are dominantly activated by single transcription factors

Cell viability depends on the precise expression of essential genes, which are controlled by CpG-island (CGI) promoters densely bound by transcription factors (TFs). This has led to the prevailing model that TFs cooperate to ensure ubiquitous expression. Here, using rapid and reversible single and combinatorial degradation in murine stem cells, we systematically dissect the regulatory interactions between five key TFs. We uncover an unexpectedly specific architecture in which regulatory dominance, rather than cooperation, is the prevailing mode, where individual TFs autonomously drive chromatin opening and gene activation at largely distinct promoters. Cooperative regulation occurs at a minority of sites with antagonistic or synergistic outcomes modulated by the interplay between nucleosome positioning and TF sensitivity to chromatin. This logic is recapitulated at synthetic sequences and reflected in human genetic variation. These findings reveal that single TFs dominantly activate distinct sets of CGI-linked genes, including essential genes, across development, homeostasis, and disease.

molecular biology↗

bioRxiv2022

Readout of histone methylation by Trim24 locally restricts chromatin opening by p53

The genomic binding sites of the transcription factor (TF) and tumour suppressor p53 are unusually diverse in regards to their chromatin features, including histone modifications, opening the possibility that chromatin provides context-dependence for p53 regulation. Here, we show that the ability of p53 to open chromatin and activate its target genes is indeed locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated lysine 4 of histone H3, thereby preferentially locating to those p53 sites that reside in closed chromatin, while it is deterred from accessible chromatin by lysine 4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to impact gene expression as a function of the local chromatin state. These findings link histone methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors which locally modulate TF function.

genomics↗

bioRxiv2018

Hi-C detects novel structural variants in HL-60 and HL-60/S4 cell lines

Cancer cell lines often have large structural variants (SVs) that evolve over time. There are many reported differences in large scale SVs between HL-60 and HL-60/S4, cell lines derived from the same acute promyelocytic leukemia sample. However, the stability and variability of inter- and intra-chromosomal SVs between different sources is unknown. Here, we used Hi-C and RNA-seq to identify and compare large SVs in HL-60 and HL-60/S4 cell lines.\n\nComparisons with previously reported karyotypes identified two non-canonical SVs in HL-60. Ten previously unreported SVs were identified in HL-60/S4. The unreported SVs were generally small enough to be plausibly undetected with traditional karyotyping methods. An expansion centered on MYC was found in a novel genomic location in HL-60. The HL-60 cell line has more within-line structural variation than the HL-60/S4 derivative cell line.\n\nHL-60 and HL-60/S4 karyotypes are generally consistent with the current literature, with some exceptions. Hic_breakfinder is an effective tool for identifying all SVs, but intra-chromosomal SVs are less reliably detected across different samples. The orientation of SV patterns, and strandedness of gene fusions, allowed us to differentiate inversions from other forms of intra-chromosomal SV. Visual inspection of Hi-C heatmap patterns allow further characterization of SVs without additional methods, although orthogonal information such as gene fusions contribute to the characterization.

genomics↗