Biology subjects

Abraham, B.

Publications and source records attributed to Abraham, B..

9 recordsLinked to original sources

bioRxiv2026

Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit

Rhabdomyosarcoma (RMS) is a multi-subtype, high-risk pediatric sarcoma with a low mutational burden. The mutations found in RMS often alter genes involved in transcriptional control. Approaches to target dysregulated RMS transcription have remained elusive. Here, we develop a novel approach to target RMS transcription comprising simultaneous targeting of two distinctly acting transcriptional co-activators. We discover a common identity-controlling pan-RMS core regulatory circuit (CRC) composed of oncogenic and lineage-specific myogenic master transcription factors (mTFs). Using a super-enhancer-based reporter screen, we identify the EP300/CBP inhibitor A485 as a potent inhibitor of the pan-RMS CRC, though with efficacy-limiting toxicities. To enhance efficacy, we identify the mTF-binding co-activator EYA2 as a co-factor of this pan-RMS CRC and exploit a new second-generation EYA1/2 inhibitor, LG1-34, to disrupt its function. Combined co-activator inhibition inactivates the CRC and synergistically reduces RMS growth. This strategy dually targets CRC-associated co-activators to cooperatively suppress the RMS transcriptome and enforce cell death.

cancer biology↗

bioRxiv2026

Api5 Regulates Genomic Stability and Chemotherapy Resistance in Cancer

Api5 is elevated in a number of cancers and is associated with many hallmarks of cancer, including resistance to apoptosis, immune escape, stemness, chemotherapy resistance, high proliferation, and cell-cycle dysregulation. In this study, we identified the DNA and chromatin-binding activities of Api5 in tumorigenic cells, as well as its association with genomic instability and chemotherapy resistance. Knockdown of Api5 resulted in reduced nuclear volume, DNA content, and chromosome number, and increased sensitivity to DNA damage. The survival of Api5-knockdown cells decreased following UV and cisplatin treatments due to the accumulation of damaged DNA and inefficient nucleotide excision repair. Interestingly, Api5 knockdown cells also exhibited low pChk1 levels following UV damage. Further, we confirmed the chemotherapy resistance phenotype in cancers with elevated Api5 levels, demonstrating that xenograft tumours with Api5 knockdown responded better to cisplatin, with significant tumour regression. SummaryApoptosis inhibitor 5 (Api5) contributes to chemotherapy resistance by conferring a survival advantage and promoting efficient DNA repair following genotoxic stress through regulation of Chk1 activation.

Cancer Biology↗

bioRxiv2025

KAT6A/B inhibition synergizes with retinoic acid and enhances the efficacy of GD2-targeted immunotherapy in neuroblastoma

High-risk neuroblastoma accounts for about 15% of childhood cancer deaths and arises from precursors of the peripheral sympathetic nervous system. Retinoids are clinically used to inhibit growth of neuroblastoma cells through reconfiguration of the regulatory enhancer landscape. Its effects, however, are completely reversible after drug withdrawal, leading to rapid tumor cell proliferation. Here, we sought to identify epigenetic modifiers that potentiate the antiproliferative effects of retinoids in neuroblastoma. We identified PF-9363, an inhibitor of the histone H3K23 acetyltransferases KAT6A/B, as synergistically inhibiting neuroblastoma growth in combination with retinoids. PF-9363 plus retinoids induces durable growth arrest, which persists beyond retinoid withdrawal in vitro and in vivo with sustained Polycomb-mediated repression of oncogenic transcription factors MYCN, PHOX2B and GATA3. Moreover, PF-9363 plus retinoids increases GD2 expression, rendering neuroblastoma cells more sensitive to anti-GD2 immunotherapy. Overall, our studies demonstrate that KAT6A/B inhibition increases the effectiveness of retinoids and GD2-targeted immunotherapy in neuroblastoma.

cancer biology↗

bioRxiv2024

Topology-informed regulatory element collections coordinate cell identity gene expression programs

Transcription proteins are concentrated at nuclear transcriptional condensates. These condensates contain cis-regulatory elements (CREs), including enhancers and promoters, that are thought to regulate genes in the same condensate. The roles of condensates are of great current interest, but research into their function is limited by an inability to comprehensively identify their associated CREs. Here, we present a conceptual framework and algorithm, BOUQUET, for integrating genome topology, chromatin occupancy, and graph theory to associate CREs and transcription protein machinery with target genes and identify exceptionally protein-rich communities that interact with condensates. BOUQUET uncovers surprising quantitative correlations between community protein accumulation and gene expression phenotypes by combining accurate CRE-gene assignment with co-activator binding profiles. A small subset of communities, which we call "3D-super-enhancers," is exceptionally protein-rich. BOUQUET-predicted 3D-SEs are comparable in number to co-activator nuclear puncta, and all genes known to interact with co-activator condensates in embryonic stem cells are within 3D-SEs. 3D-SEs are enriched for association with cell identity genes across mammalian tissues. Microscopy analyses show frequent co-localization and co-expression of genes from the same 3D-SE within a single co-activator punctum, suggesting 3D-SE components interact with co-activator condensates. Thus 3D-SEs correspond to co-activator puncta, which nominates additional condensate-associated genes and CREs.

molecular biology↗

bioRxiv2023

Changes in local interaction rules during ontogeny underlie the evolution of collective behavior

Collective motion emerges from individual interactions which produce groupwide patterns in behavior. While adaptive changes to collective motion are observed across animal species, how local interactions change when these collective behaviors evolve is poorly understood. Here, we use the Mexican tetra, A. mexicanus, which exists as a schooling surface form and a non-schooling cave form, to study differences in how fish alter their swimming in response to neighbors across ontogeny and between evolutionarily diverged populations. We find that surface fish undergo a transition to schooling during development that occurs through increases in inter-individual alignment and attraction mediated by changes in the way fish modulate speed and turning relative to neighbors. Cavefish, which have evolved loss of schooling, exhibit neither of these schooling-promoting interactions at any stage of development. These results reveal how evolution alters local interaction rules to produce striking differences in collective behavior.

evolutionary biology↗

bioRxiv2023

Genetic Predisposition to Neuroblastoma Results from a Regulatory Polymorphism that Promotes the Adrenergic Cell State

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like "mesenchymal" cell state and a more differentiated sympathetic "adrenergic" cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional co-factor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism G/T that affects a GATA motif in the first intron of LMO1. Here we show that wild-type zebrafish with the GATA genotype develop adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduces the penetrance of MYCN-driven tumors, which are restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrates that TATA/TATA tumors also exhibit a mesenchymal cell state and are low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduces the neuroblastoma initiation rate by preventing formation of the adrenergic cell state, a mechanism that is conserved over 400 million years of evolution separating zebrafish and humans.

cancer biology↗

bioRxiv2022

A nuclear receptor facilitates differentiation of human PSCs into more mature hepatocytes

The capacity to generate functional hepatocytes from renewable human pluripotent stem cells (hPSCs) could address limited supplies of primary human hepatocytes. However, hepatocytes differentiated from hPSCs in vitro are functionally immature. To understand mechanisms regulating maturation of in vitro derived hepatocytes, we developed a 3D spheroid differentiation system and compared gene regulatory elements in uncultured human primary hepatocytes with those in hepatocytes that were differentiated in 2D or 3D conditions from human PSCs by RNA-seq, ATAC-seq, and H3K27Ac ChIP-seq. Three-dimensional differentiation improved enhancer activity and expression of transcription factor ONECUT1, but was insufficient to upregulate human-specific mature hepatocytes marker gene CYP3A4 or super-enhancer regulated transcription factor gene NFIC. Regulome comparisons showed reduced enrichment of thyroid receptor THRB motifs in accessible chromatin and in active enhancers without reduced transcription of THRB, suggesting the regulation at the level of THRB ligands in PSC-differentiated hepatocytes. Addition of thyroid hormone T3 to the PSC-differentiated hepatocytes increased CYP3A4 expression. T3 increased binding of THRB to the CYP3A4 proximal enhancer and restored the super-enhancer status and gene expression of NFIC and reduced expression of AFP. The resultant hPSC-hepatocytes showed gene expression, epigenetic status and super-enhancer landscape closer to primary hepatocytes and activated regulatory regions including non-coding SNPs associated with liver-related diseases. Transplanting the 3D PSC-hepatocytes into immunocompromised mice resulted in engraftment of human hepatocytes in the mouse liver parenchyma without disrupting normal liver histology at 6 months after transplantation. This work provides insights into the functions of nuclear receptor THRB and highlights the importance of the environmental factors-nuclear receptors axis in regulating maturation of human PSC-differentiated cell types.

developmental biology↗

bioRxiv2020

Acetylation of isoniazid - a novel mechanism of isoniazid resistance in Mycobacterium tuberculosis

Isoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a pro-drug which is converted into its active form by the intracellular KatG enzyme of Mycobacterium tuberculosis. The activated drug hinders cell wall biosynthesis by inhibiting InhA protein. INH resistant strains of M. tuberculosis usually have mutations in katG, inhA, ahpC, kasA, and ndh genes. However, INH resistant strains which do not have mutations in any of these genes are reported, suggesting that these strains may adopt some other mechanism to become resistant to INH. In the present study we characterized Rv2170, a putative acetyltransferase in M. tuberculosis, to elucidate its role in inactivating isoniazid. The purified recombinant protein was able to catalyze transfer of acetyl group to INH from acetyl CoA. HPLC and LC-MS analyses showed that following acetylation by Rv2170, INH is broken down into isonicotinic acid and acetylhydrazine. Drug susceptibility assay and confocal analysis showed that M. smegmatis, which is susceptible to INH, is not inhibited by INH acetylated with Rv2170. Recombinant M. smegmatis and M. tuberculosis H37Ra overexpressing Rv2170 were found to be resistant to INH at minimum inhibitory concentrations that inhibited wildtype strains. In addition, intracellular M. tuberculosis H37Ra overexpressing Rv2170 survived better in macrophages when treated with INH. Our results strongly indicate that Rv2170 acetylates INH, and this could be one of the strategies adopted by at least some M. tuberculosis strains to overcome INH toxicity.

biochemistry↗

bioRxiv2018

Short-term effectiveness of HIV care coordination among persons with recent HIV diagnosis or history of poor HIV outcomes

The New York City HIV Care Coordination Program (CCP) combines multiple evidence-based strategies to support persons living with HIV (PLWH) at risk for, or with a recent history of, poor HIV outcomes. We assessed the comparative effectiveness of the CCP by merging programmatic data on CCP clients with population-based surveillance data on all New York City PLWH. A non-CCP comparison group of similar PLWH who met CCP eligibility criteria was identified using surveillance data. The CCP and non-CCP groups were matched on propensity for CCP enrollment within four baseline treatment status groups (newly diagnosed or previously diagnosed and either consistently unsuppressed, inconsistently suppressed or consistently suppressed). We compared CCP to non-CCP proportions with viral load suppression at 12-month follow-up. Among the 13,624 persons included, 15{middle dot}3% were newly diagnosed; among the 84{middle dot}7% previously diagnosed, 14{middle dot}2% were consistently suppressed, 28{middle dot}9% were inconsistently suppressed, and 41 {middle dot}6% were consistently unsuppressed in the year prior to baseline. At 12-month follow-up, 59{middle dot}9% of CCP and 53{middle dot}9% of non-CCP participants had viral load suppression (Relative Risk=1.11, 95%CI:1.08-1.14). Among those newly diagnosed and those consistently unsuppressed at baseline, the relative risk of viral load suppression in the CCP versus non-CCP participants was 1.15 (95%CI:1.09-1.23) and 1.32 (95%CI:1.23-1.42), respectively. CCP exposure shows benefits over no CCP exposure for persons newly diagnosed or consistently unsuppressed, but not for persons suppressed in the year prior to baseline. We recommend more targeted case finding for CCP enrollment and increased attention to viral load suppression maintenance.

epidemiology↗