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ATR expands embryonic stem cell fate potential in response to replication stress

Atashpaz, Sina; Samadi Shams, Sara; Gonzalez, Javier Martin; Sebestyén, Endre; Arghavanifard, Negar; Gnocchi, Andrea; Albers, Eliene; Minardi, Simone; Faga, Giovanni; Soffientini, Paolo; Allievi, Elisa; Cancila, Valeria; Bachi, Angela; Fernández-Capetillo, Óscar; Tripodo, Claudio; Ferrari, Francesco; López-Contreras, Andrés Joaquin; Costanzo, Vincenzo
Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in mouse embryonic stem cells (ESCs) that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GRSF1-dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra-embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS.
PMID: 32163370
ISSN: 2050-084x
CID: 4349202

KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs

Tzatsos, Alexandros; Paskaleva, Polina; Ferrari, Francesco; Deshpande, Vikram; Stoykova, Svetlana; Contino, Gianmarco; Wong, Kwok-Kin; Lan, Fei; Trojer, Patrick; Park, Peter J; Bardeesy, Nabeel
Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogated tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperated with KrasG12D to promote PDAC formation in mouse models. Gain- and loss-of-function experiments coupled to genome-wide gene expression and ChIP studies revealed that KDM2B drives tumorigenicity through 2 different transcriptional mechanisms. KDM2B repressed developmental genes through cobinding with Polycomb group (PcG) proteins at transcriptional start sites, whereas it activated a module of metabolic genes, including mediators of protein synthesis and mitochondrial function, cobound by the MYC oncogene and the histone demethylase KDM5A. These results defined epigenetic programs through which KDM2B subverts cellular differentiation and drives the pathogenesis of an aggressive subset of PDAC.
PMID: 23321669
ISSN: 1558-8238
CID: 2269832

The reconstruction of transcriptional networks reveals critical genes with implications for clinical outcome of multiple myeloma

Agnelli, Luca; Forcato, Mattia; Ferrari, Francesco; Tuana, Giacomo; Todoerti, Katia; Walker, Brian A; Morgan, Gareth J; Lombardi, Luigia; Bicciato, Silvio; Neri, Antonino
PURPOSE/OBJECTIVE:The combined use of microarray technologies and bioinformatics analysis has improved our understanding of biological complexity of multiple myeloma (MM). In contrast, the application of the same technology in the attempt to predict clinical outcome has been less successful with the identification of heterogeneous molecular signatures. Herein, we have reconstructed gene regulatory networks in a panel of 1,883 samples from MM patients derived from publicly available gene expression sets, to allow the identification of robust and reproducible signatures associated with poor prognosis across independent data sets. EXPERIMENTAL DESIGN/METHODS:Gene regulatory networks were reconstructed by using Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) and microarray data from seven MM data sets. Critical analysis of network components was applied to identify genes playing an essential role in transcriptional networks, which are conserved between data sets. RESULTS:Network critical analysis revealed that (i) CCND1 and CCND2 were the most critical genes; (ii) CCND2, AIF1, and BLNK had the largest number of connections shared among the data sets; (iii) robust gene signatures with prognostic power were derived from the most critical transcripts and from shared primary neighbors of the most connected nodes. Specifically, a critical-gene model, comprising FAM53B, KIF21B, WHSC1, and TMPO, and a neighbor-gene model, comprising BLNK shared neighbors CSGALNACT1 and SLC7A7, predicted survival in all data sets with follow-up information. CONCLUSIONS:The reconstruction of gene regulatory networks in a large panel of MM tumors defined robust and reproducible signatures with prognostic importance, and may lead to identify novel molecular mechanisms central to MM biology.
PMID: 21890453
ISSN: 1078-0432
CID: 3647842

The Lkb1 metabolic sensor maintains haematopoietic stem cell survival

Gurumurthy, Sushma; Xie, Stephanie Z; Alagesan, Brinda; Kim, Judith; Yusuf, Rushdia Z; Saez, Borja; Tzatsos, Alexandros; Ozsolak, Fatih; Milos, Patrice; Ferrari, Francesco; Park, Peter J; Shirihai, Orian S; Scadden, David T; Bardeesy, Nabeel
Haematopoietic stem cells (HSCs) can convert between growth states that have marked differences in bioenergetic needs. Although often quiescent in adults, these cells become proliferative upon physiological demand. Balancing HSC energetics in response to nutrient availability and growth state is poorly understood, yet essential for the dynamism of the haematopoietic system. Here we show that the Lkb1 tumour suppressor is critical for the maintenance of energy homeostasis in haematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all haematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The haematopoietic effects are largely independent of Lkb1 regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling. Instead, these data define a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in haematopoietic cells through a novel metabolic checkpoint.
PMID: 21124451
ISSN: 1476-4687
CID: 4961852