Biology subjects

Zekri, Y.

Publications and source records attributed to Zekri, Y..

4 recordsLinked to original sources

bioRxiv2025

IRE1 activity regulates tumour and microenvironment cell lineage states while stratifying localised and metastatic prostate cancer.

Prostate cancer (PCa) is an androgen receptor (AR) driven, high-incidence disease significantly contributing to cancer mortality. PCa is in need of better risk stratification at diagnosis and treatment outcomes in patients at high risk of metastasis. The unfolded protein response (UPR) is an AR-dependent process. However, the impact of the UPR transducer IRE1 on AR-dependent biology and treatment resistance has not been defined. We use diverse pre-clinical models of stress response to describe IRE1 activity impact on multiple disease stages and demonstrate its involvement with poor prognosis (RB1 loss), and cell lineage determination (club phenotypes). Integrating clinical transcriptomic datasets, we chart IRE1 activity throughout PCa evolution by developing a PCa-specific, IRE1 activity gene set (IRE1_18) reflecting both tumoral and micro-environmental niches. IRE1_18 can determine tumoral identity, inform androgen deprivation treatment suitability, prognosticate localised and metastatic disease independently from AR activity, and guide IRE1 modulation as a novel combination therapeutic. Graphical Abstract created using Biorender.com O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/643042v3_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@18edd6aorg.highwire.dtl.DTLVardef@6a759eorg.highwire.dtl.DTLVardef@14ff3fborg.highwire.dtl.DTLVardef@1ae77d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

An atlas of thyroid hormone receptors target genes in mouse tissues

We gathered in a single database available RNA-seq and ChIP-seq data to better characterize the target genes of the thyroid hormone receptors in several cell types. This database can serve as a resource to analyze the mode of action of the hormone. Also, it is an easy-handling convenient tool to obtain information on specific genes in regards to T3 regulation, or extract larger list of genes of interest based on the users criteria. Overall, this atlas is a unique compilation of recent sequencing data focusing on thyroid hormones, their receptors, mode of action, targets and roles which may profit researchers within the field. A preliminary analysis indicates extensive variations in the repertoire of target genes which transcription is upregulated by chromatin-bound nuclear receptor. Although it has a major influence, chromatin accessibility is not the only parameter that determines the cellular selectivity of hormonal response.

genomics↗

bioRxiv2022

Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice

Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3-signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT. Significance StatementThyroid hormones (TH) increase energy expenditure by regulating the expression of target genes in many metabolic tissues. Among them, brown adipose tissue (BAT) dissipates biochemical energy into heat production to notably prevent hypothermia during cold exposure. Hypothyroid mice display inefficient BAT thermogenesis suggesting that TH are crucial for this process. Here, we eliminated TH signaling specifically in brown adipocytes and expose the mice to different physiological stressors. We showed that TH signaling is crucial for BAT thermogenesis as it controls the expression of genes involved in proliferation and in the metabolism of lipids and glucose, the main energy resources for BAT thermogenesis. This study provides an unprecedented view on the pathways by which T3 activates energy expenditure the BAT.

genomics↗

bioRxiv2020

In vitro assessment of the capacity of pesticides to act as agonists/antagonists of the thyroid hormone nuclear receptors.

Several in vitro tests, including transcriptome analysis of neural cells, were performed to assess the capacity of 33 pesticides to act as thyroid hormone disruptors (THD). Although some pesticides elicit a cellular response, which interferes with thyroid hormone signaling, we found no evidence that they can act as receptor agonists or antagonists. We conclude that the nuclear receptors of thyroid hormone are not common targets of THD, and that pesticide neurodevelopmental toxicity is not explained by a general alteration of neural cell response to thyroid hormone.

pharmacology and toxicology↗