Biology subjects

Pessa, J. C.

Publications and source records attributed to Pessa, J. C..

3 recordsLinked to original sources

bioRxiv2024

Waves of transcription drive erythroid differentiation and launch the NRF2-activated antioxidant program

Transcriptional reprogramming drives differentiation and coordinates cellular responses. While mRNA expression in distinct cell types has been extensively analyzed, the mechanisms that control RNA synthesis upon lineage specifications remain unclear. Here, we induce erythroid differentiation in human cells, track transcription and its regulation at nucleotide-resolution, and identify molecular mechanisms that orchestrate gene and enhancer activity during erythroid specification. We uncover waves of transcription and reveal that a brief differentiation signal launches sustained and propagating changes in RNA synthesis and mRNA expression over cell divisions. NRF2, a strong trans-activator upon oxidative stress, drives erythroid differentiation without a detectable increase in reactive oxygen species. In erythroid precursors, NRF2 induces architecturally primed, differentiation-linked enhancers, and genes encoding globin and antioxidant proteins. Projecting signal-induced transcription to DNA accessibility and mRNA expression in single human bone marrow cells, reveals ordered activation of myeloid (GABPA) and erythroid (GATA1, TAL1 and HEMGN) factors in lineage-specification, followed by NRF2-triggered antioxidant response in the late erythroid cells. This study establishes molecular mechanisms that prime, execute, and temporally coordinate RNA synthesis during erythroid differentiation. Furthermore, we show that master regulators of differentiation and stress co-orchestrate erythropoiesis and produce the antioxidant machinery before erythroid cells mature to oxygen transporting enucleated erythrocytes.

genomics↗

bioRxiv2024

Dynamic HSF2 regulation drives breast cancer progression by steering the balance between proliferation and invasion

Phenotypic plasticity is a hallmark of breast carcinogenesis that facilitates the acquisition of invasive properties via epithelial-mesenchymal transition (EMT). Transforming growth factor-beta (TGF-{beta}), a key EMT-inducing cytokine, drives pro-metastatic gene programs through downstream transcription factors. Among mammalian stress-protective transcription factors, heat shock factor 2 (HSF2) has been associated with cancer progression, but the mechanisms regulating HSF2 expression and activity are unknown. Here, we demonstrate that TGF-{beta} stimulation downregulates HSF2 to enable activation of an invasive phenotype. Remarkably, ectopic expression of HSF2 in breast cancer cells inhibited TGF-{beta}-mediated effects on gene expression and cellular properties. By using both in vitro cell models and in vivo zebrafish xenografts, we found that a temporal downregulation of HSF2 is a prerequisite for EMT activation, while ectopically sustained HSF2 promotes rapid cell proliferation and survival. Analyses of human patient tissues corroborated our results by showing that HSF2 is dynamically regulated during breast cancer progression. Specifically, HSF2 expression and nuclear co-localization with the proliferation marker Ki67 are dramatically increased already in ductal carcinoma in situ. Altogether, our findings expand the pathological landscape of HSF2, demonstrating that dynamic regulation of HSF2 is an inherent property of malignant progression and characterizes the distinct stages of breast cancer.

cell biology↗

bioRxiv2022

A subpopulation of Talin 1 resides in the nucleus and regulates gene expression

Talin 1 (TLN1) is best known for its role at focal adhesions, where it activates {beta}-integrin receptors and transmits mechanical stimuli to the actin cytoskeleton. Interestingly, the localization of TLN1 is not restricted to the focal adhesions, but its function in other cellular compartments remains poorly understood. By utilizing both biochemical and confocal microscopy analyses, we show that TLN1 localizes to the nucleus and that it strongly interacts with the chromatin. Importantly, depletion of endogenous TLN1 results in extensive changes in the gene expression profile of human breast epithelial cells. To determine the impact of nuclear TLN1 on gene regulation, we expressed a TLN1 fusion protein containing a nuclear localization signal. Our results revealed that nuclear TLN1 regulates a specific subset of the TLN1-dependent genes. Taken together, we show that apart from localizing at the plasma membrane and cytoplasm, TLN1 also resides in the nucleus where it functions in the regulation of gene expression.

molecular biology↗