Biology subjects

Gaber, M. W.

Publications and source records attributed to Gaber, M. W..

3 recordsLinked to original sources

bioRxiv2026

Transcriptional and DNA Methylation Changes in the Hippocampus and Prefrontal Cortex after Fractionated Cranial Radiation in Mice

Fractionated whole-brain irradiation is essential for treating brain tumors, but many long-term survivors develop cognitive decline whose molecular basis is poorly understood. We asked which cell types and gene programs change late after irradiation, how the hippocampus and prefrontal cortex compare, and whether DNA methylation changes affect the same genes or programs. Male and female mice received whole-brain irradiation (5 x 4 Gy) or anesthesia alone. Irradiated mice showed persistent deficits in executive function and spatial memory. Eleven weeks after irradiation, single-nucleus RNA sequencing and whole-genome bisulfite sequencing of pooled hippocampal (CA1-3) and prefrontal tissue showed cell-type-specific transcriptional changes in neurons of both regions. Both regions showed reduced ribosomal-protein gene expression and changes in adhesion genes, with reduced respiratory-chain genes in prefrontal neurons and bidirectional synaptic gene changes in hippocampus. Differentially methylated regions were enriched at promoters, with hypermethylation predominating in three of the four sex-by-region contrasts. Methylation and gene expression changes pointed to overlapping synaptic and signaling programs, largely through different genes.

neuroscience↗

bioRxiv2025

Anti-CSF-1R therapy with combined immuno- chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched Triple Negative Breast Cancers

Patients diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory metronomic Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic syngeneic Trp53 null TNBC genetically engineered mouse models (GEMMs) that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-15 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.

cancer biology↗

bioRxiv2024

Coordinated regulation by lncRNAs results in tight lncRNA-target couplings

The determination of long non-coding RNA (lncRNA) function is a major challenge in RNA biology with applications to basic, translational, and medical research [1-7]. Our efforts to improve the accuracy of lncRNA-target inference identified lncRNAs that coordinately regulate both the transcriptional and post-transcriptional processing of their targets. Namely, these lncRNAs may regulate the transcription of their target and chaperone the resulting message until its translation, leading to tightly coupled lncRNA and target abundance. Our analysis suggested that hundreds of cancer genes are coordinately and tightly regulated by lncRNAs and that this unexplored regulatory paradigm may propagate the effects of non-coding alterations to effectively dysregulate gene expression programs. As a proof-of-principle we studied the regulation of DICER1 [8, 9]--a cancer gene that controls microRNA biogenesis--by the lncRNA ZFAS1, showing that ZFAS1 activates DICER1 transcription and blocks its post-transcriptional repression to phenomimic and regulate DICER1 and its target microRNAs.

bioinformatics↗