Biology subjects

Sandlesh, P.

Publications and source records attributed to Sandlesh, P..

4 recordsLinked to original sources

bioRxiv2024

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4+ T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

cancer biology↗

bioRxiv2021

FACT-mediated maintenance of chromatin integrity during transcription is essential for viability of mammalian stem cells

Preservation of nucleosomes during replication has been extensively studied, while the maintenance of nucleosomes during transcription has gotten less attention. The histone chaperone FACT is involved in transcription elongation, although whether it disassembles or assembles nucleosomes during this process is still unclear. We deleted the FACT subunit in adult mice to clarify the function of FACT in mammals. FACT loss was lethal due to the loss of the earliest progenitors in bone marrow and intestine, while mor differentiated cells were not affected. Using cells isolated from several tissues, we showed that FACT loss was lethal only for stem cells but not cells differentiated in vitro. FACT depletion led to increased chromatin accessibility in a transcription-dependent manner, suggesting that nucleosomes are lost during transcription in the absence of FACT. The most prominent response to the loss of nucleosomes was the activation of interferon signaling and the accumulation of immunocytes in sensitive organs. FACT maintained chromatin integrity during transcription in mammalian adult stem cells, suggesting that chromatin transcription in these cells is different from more differentiated cells.

systems biology↗

bioRxiv2018

Prevention of chromatin destabilization by FACT is crucial for malignant transformation

Expression of histone chaperone FACT is increased in tumors and associated with poor prognosis. We investigated why aggressive tumor cells need FACT using a model where FACT could be turned off and confirmed that while FACT is not essential for non-tumor cells, cells become dependent on FACT following oncogene-induced transformation. We compared the phenotypic and transcriptional changes induced by FACT loss and excluded a direct role for FACT in the transcription of genes essential for the viability of transformed cells. Moreover, we established that in immortalized and transformed cells, FACT has a weak negative effect on gene expression. At the same time, we observed a positive correlation between FACT enrichment and the rate of transcription, which was consistent with previous reports. To explain these puzzling observations, we hypothesized that FACT does not facilitate transcription elongation in transformed cells, but prevents nucleosome loss associated with transcription. Indeed, we observed destabilization of chromatin in immortalized and transformed cells upon FACT loss. Furthermore, transformed cells had less stable chromatin than non-transformed cells, which made them vulnerable to FACT loss. However, the mechanisms of cell death upon chromatin destabilization needs to be established. Our data suggest that malignant transformation is accompanied by general chromatin destabilization, and FACT prevents irredeemable chromatin loss.

cell biology↗

bioRxiv2017

TRAIN in response to treatment with anti-cancer small molecule destabilizing chromatin

The anticancer activity of genotoxic agents has been intensively studied, while the mechanisms of action of drugs destabilizing the epigenome are far less understood. We previously found that DNA hypomethylation in the absence of p53 leads to transcriptional desilencing of repetitive DNA elements, such as pericentromeric repeats and endogenous retroelements, which is associated with an interferon type I response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, a small molecule anticancer drug candidate, which destabilizes nucleosomes via disruption of histone/DNA interactions, can induce TRAIN independently of the p53 status of a cell. Furthermore, curaxin inhibits oncogene-induced transformation in an interferon-dependent manner, suggesting that cancer prevention by curaxin, previously attributed to its p53-activating and NF-kappaB-inhibiting activities, may also involve the induction of the interferon response to epigenetic derepression of the cellular \"repeatome.\" Moreover, we observed that another type of drugs decondensing chromatin, histone deacetylase inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of cells via elimination of cells with desilenced chromatin.

molecular biology↗