Biology subjects

Mukherji, A.

Publications and source records attributed to Mukherji, A..

3 recordsLinked to original sources

bioRxiv2026

Not all tumors age alike: Bidirectional epigenetic age shifts across 20 solid tumors

Epigenetic ageing and tumor progression have each been studied extensively using DNA methylation, yet their relationship remains poorly understood. Here we integrate DNA methylation age estimation with phyloepigenetic reconstruction across 20 solid cancer spanning 1710 samples from The Cancer Genome Atlas to assess age acceleration in tumor tissue compared to matched normal tissue. MethodsDNA methylation age was estimated for 544 patients with matched normal and tumor samples using Horvaths epigenetic clock, with linear regression used to assess correspondence to chronological age and Wilcoxon signed-rank tests evaluated whether tumor-normal age differences deviated significantly from zero. Tumor evolutionary architecture was reconstructed via UPGMA clustering of genome-wide methylation divergence into phyloepigenetic trees, from which trunk and private methylation events were classified and their chromosomal distribution compared descriptively across cancer types. ResultsApplying Horvaths epigenetic clock to normal tissue yielded a mean absolute error of 17.6 years, substantially exceeding expectations. Contrary to previous reports of pronounced tumor age acceleration any ubiquitous pattern of acceleration did not emerge at the cohort level across all tumor types when tumor age was compared directly against matched normal tissue. Acceleration and deceleration instead varied often consistently by cancer types, with significant positive differences observed in endometrial, lung squamous, head and neck, and prostate cancers, and significant negative differences in renal and thyroid cancers. Phyloepigenetic reconstruction revealed that methylation events arose predominantly through private, subclonal branching rather than early clonal events. The X chromosome was found overrepresented among methylation events across nearly all solid cancers. ConclusionEpigenetic aging in cancer is not uniform or consistently accelerated but reflects tissue-specific and often opposing patterns of change. The predominance of subclonal events suggest ongoing epigenetic diversification throughout tumor evolution, while the consistent overrepresentation of X-chromosome events indicates a distinct chromosome-level vulnerability.

genetics↗

bioRxiv2025

Hepatocyte ERα orchestrates sex-specific liver adaptation to fasting and feeding states

Sex differences in hepatic physiology are thought to influence individual susceptibility to chronic liver diseases including Metabolic-Associated Steatotic Liver Disease (MALSD). Previous studies demonstrated the central contribution of estrogens which primarily influence liver biology through the activation of Estrogen Receptor alpha (ER). However, how ER signaling in hepatocyte modulates liver functions according to the nutritional status, a critical determinant of hepatic metabolism, remains to be characterized. The present study first reveals the nycthemeral expression profile of liver ER, which peaks during the feeding period (ZT16) in both male and female mice. ER expression is altered by reprogramming the hepatic circadian clock in response to inverted food intake, highlighting the influence of feeding on liver ER expression patterns. As ER is mainly expressed in hepatocytes both in human and mouse livers, the functional role of hepatocyte ER during fasting or feeding state was then delineated, using mice harboring ER hepatocyte-specific deletion (ERhep-/-) compared with their wild-type littermates (ERhep+/+). Transcriptomic analyses reveal significant sex differences in the adaptation of liver functions to this contrasted nutritional status, as well as the sex-specific regulatory effects of hepatocyte ER. In such physiological settings, hepatocyte ER deletion does not influence liver transcriptomic profiles in males but significantly alters gene expression in female livers, both fed and fasted conditions. Hepatocyte ER more specifically controls genes associated with inflammatory responses and fatty acid metabolic pathways in females, modulating the ChREBP and PPAR pathways in feeding or fasting states, respectively. Thus, hepatocyte ER is integral to liver metabolic adaptations to fasting and feeding in females but not in males, thus exhibiting both sex-specific and diet-dependent actions. Further characterizing sex differences in liver metabolic flexibility, these results provide new information to develop sex-based strategies for the prevention and management of MASLD.

physiology↗

bioRxiv2023

ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide co-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Statement of SignificanceThis study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2s oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.

cancer biology↗