Biology subjects

Davis, M. B.

Publications and source records attributed to Davis, M. B..

3 recordsLinked to original sources

bioRxiv2022

Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A

BackgroundAfrican American (AA) prostate cancer (PCa) appears uniquely sensitive to 1,25(OH)2D3 signaling, compared to European American (EA) PCa, but the extent and impact of vitamin D receptor genomic functions remain poorly defined. ResultsA panel of EA and AA prostate epithelial cells (EA: HPr1-AR, LNCaP, AA: RC43N, RC43T, RC77N, RC77T) were analyzed with RIME to reveal the cell-specific composition of the VDR- complex. 1,25(OH)2D3-dependent ATAC-Seq revealed the greatest impact on nucleosome positioning in RC43N and RC43T, with gain of nucleosome-free at enhancer regions. VDR ChIP-Seq identified stronger and more frequent VDR binding in RC43N and RC43T that was enriched for a larger and distinct motif repertoire, than EA cells. VDR binding significantly overlapped with core circadian rhythm transcription factors in AA cell line models. RNA-Seq also revealed significantly stronger 1,25(OH)2D3 dependent VDR transcriptional responses enriched for circadian rhythm and inflammation networks in AA cells. Whilst RC43N was most responsive, RC43T displayed distorted responses. Significantly reduced BAZ1A/SMARCA5 in AA PCa samples was identified, and restored BAZ1A expression uniquely and significantly increased 1,25(OH)2D3-regulated VDR targets in AA cells. These VDR- dependent cistrome-annotated genes were also uniquely and most significantly identified in three cohorts of AA PCa patients. ConclusionThese data suggest VDR transcriptional control in the prostate is more potent and dynamic in AA men, and primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmentally-regulated serum vitamin D3 levels suppress these actions. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes including stress responses, access to quality early detection and treatment, social determinants and that collectively contribute to PCa health disparities.

cancer biology↗

bioRxiv2021

Dual Roles for Nuclear RNAi Argonautes in C. elegans Dosage Compensation

Dosage compensation involves chromosome-wide gene regulatory mechanisms which impact higher order chromatin structure and are crucial for organismal health. Using a genetic approach, we identified Argonaute genes which promote dosage compensation in C. elegans. Dosage compensation in C. elegans hermaphrodites is initiated by the silencing of xol-1 and subsequent activation of the Dosage Compensation Complex (DCC) which binds to both hermaphrodite X chromosomes and reduces transcriptional output by twofold. A hallmark phenotype of dosage compensation mutants is decondensation of the X chromosomes. We characterized this phenotype in Argonaute mutants using X chromosome paint probe and fluorescence microscopy. We found that while nuclear Argonaute mutants hrde-1 and nrde-3 exhibit de-repression of xol-1 transcripts, they also effect X chromosome condensation in a xol-1-independent manner. We also characterized the physiological contribution of Argonaute genes to dosage compensation using genetic assays and find that hrde-1 and nrde-3, together with the piRNA Argonaute prg-1, contribute to healthy dosage compensation both upstream and downstream of xol-1.

genetics↗

bioRxiv2021

Wiring logic of the early rodent olfactory system revealed by high-throughput sequencing of single neuron projections

The structure of neuronal connectivity often provides insights into the relevant stimulus features, such as spatial location, orientation, sound frequency, etc1-6. The olfactory system, however, appears to lack structured connectivity as suggested by reports of broad and distributed connections both from the olfactory bulb to the piriform cortex7-22 and within the cortex23-25. These studies have inspired computational models of circuit function that rely on random connectivity26-33. It remains, nonetheless, unclear whether the olfactory connectivity contains spatial structure. Here, we use high throughput anatomical methods (MAPseq and BARseq)34-38 to analyze the projections of 5,309 bulb and 30,433 piriform cortex output neurons in the mouse at single-cell resolution. We identify previously unrecognized spatial organization in connectivity along the anterior-posterior axis (A-P) of the piriform cortex. We find that both the bulb projections to the cortex and the cortical outputs are not random, but rather form gradients along the A-P axis. Strikingly, these gradients are matched: bulb neurons targeting a given location within the piriform cortex co-innervate extra-piriform regions that receive strong inputs from neurons within that piriform locus. We also identify signatures of local connectivity in the piriform cortex. Our findings suggest an organizing principle of matched direct and indirect olfactory pathways that innervate extra-piriform targets in a coordinated manner, thus supporting models of information processing that rely on structured connectivity within the olfactory system.

neuroscience↗