The epigenetic landscape in intestinal stem cells and its deregulation in colorectal cancer.

Epigenetic mechanisms play a pivotal role in controlling gene expression and cellular plasticity in both normal physiology and pathophysiological conditions. These mechanisms are particularly important in the regulation of stem cell self-renewal and differentiation, both in embryonic development and within adult tissues. A prime example of this finely tuned epigenetic control is observed in the gastrointestinal lining, where the small intestine undergoes renewal approximately every 3-5 days.

regulates one-carbon metabolism and histone methylation in ground-state pluripotency.

Understanding mechanisms of epigenetic regulation in embryonic stem cells (ESCs) is of fundamental importance for stem cell and developmental biology. Here, we identify , a member of the ETS family of transcription factors (TFs), as a marker of ground state pluripotency. We show that is rapidly induced in ground state ESCs and in response to extracellular signal-regulated kinase (ERK) inhibition.

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3.

Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network.

Functional role of lncRNAs in gastrointestinal malignancies: the peculiar case of small nucleolar RNA host gene family.

Long noncoding RNAs (lncRNAs) play crucial roles in normal physiology and are often de-regulated in disease states such as cancer. Recently, a class of lncRNAs referred to as the small nucleolar RNA host gene (SNHG) family have emerged as important players in tumourigenesis. Here, we discuss new findings describing the role of SNHGs in gastrointestinal tumours and summarize the three main functions by which these lncRNAs promote carcinogenesis, namely: competing with endogenous RNAs, modulating protein function, and regulating epigenetic marking.

Deregulation of Transcriptional Enhancers in Cancer.

Epigenetic regulations can shape a cell's identity by reversible modifications of the chromatin that ultimately control gene expression in response to internal and external cues. In this review, we first discuss the concept of cell plasticity in cancer, a process that is directly controlled by epigenetic mechanisms, with a particular focus on transcriptional enhancers as the cornerstone of epigenetic regulation. In the second part, we discuss mechanisms of enhancer deregulation in adult stem cells and epithelial-to-mesenchymal transition (EMT), as two paradigms of cell plasticity that are dependent on epigenetic regulation and serve as major sources of tumour heterogeneity.

WNT-Regulated Transcriptional Enhancers and Stem Cell Plasticity.

Enhancer reprogramming lies at the heart of dynamic cellular processes such as differentiation and tumorigenesis. WNT signaling is an evolutionary conserved pathway that exploits transcriptional enhancers to control the state-specific transcriptional program. Recent evidences suggest several mechanisms that govern this state-specific enhancer regulation in stem cells and cancer.

STARR-seq identifies active, chromatin-masked, and dormant enhancers in pluripotent mouse embryonic stem cells.

Background: Enhancers are distal regulators of gene expression that shape cell identity and control cell fate transitions. In mouse embryonic stem cells (mESCs), the pluripotency network is maintained by the function of a complex network of enhancers, that are drastically altered upon differentiation. Genome-wide chromatin accessibility and histone modification assays are commonly used as a proxy for identifying putative enhancers and for describing their activity levels and dynamics.

The translational landscape of ground state pluripotency.

Translational control plays a central role in regulation of gene expression and can lead to significant divergence between mRNA- and protein-abundance. Here, we used genome-wide approaches combined with time-course analysis to measure the mRNA-abundance, mRNA-translation rate and protein expression during the transition of naïve-to-primed mouse embryonic stem cells (ESCs). We find that the ground state ESCs cultured with GSK3-, MEK-inhibitors and LIF (2iL) display higher ribosome density on a selective set of mRNAs.

Dynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency.

Clusters of enhancers, referred as to super-enhancers (SEs), control the expression of cell identity genes. The organisation of these clusters, and how they are remodelled upon developmental transitions remain poorly understood. Here, we report the existence of two types of enhancer units within SEs typified by distinctive CpG methylation dynamics in embryonic stem cells (ESCs).

Ectopic activation of WNT signaling in human embryonal carcinoma cells and its effects in short- and long-term in vitro culture.

Human embryonal carcinoma (EC) cells comprise the pluripotent stem cells of malignant non-seminomatous germ cell tumors (GCTs) and represent the malignant counterpart of embryonic stem cells (ESCs). WNT/β-catenin signaling has been implicated in regulating adult and embryonic stem cells although its role in EC cells is less investigated. Here, we studied WNT signaling in a panel of representative pluripotent and nullipotent human EC cell lines.

Publisher Correction: Epigenetic modulation of a hardwired 3D chromatin landscape in two naive states of pluripotency.

In the version of the article originally published, extra lines were displayed in Fig. 7. Fig.

Epigenetic modulation of a hardwired 3D chromatin landscape in two naive states of pluripotency.

The mechanisms underlying enhancer activation and the extent to which enhancer-promoter rewiring contributes to spatiotemporal gene expression are not well understood. Using integrative and time-resolved analyses we show that the extensive transcriptome and epigenome resetting during the conversion between 'serum' and '2i' states of mouse embryonic stem cells (ESCs) takes place with minimal enhancer-promoter rewiring that becomes more evident in primed-state pluripotency. Instead, differential gene expression is strongly linked to enhancer activation via H3K27ac.

Queuine links translational control in eukaryotes to a micronutrient from bacteria.

In eukaryotes, the wobble position of tRNA with a GUN anticodon is modified to the 7-deaza-guanosine derivative queuosine (Q34), but the original source of Q is bacterial, since Q is synthesized by eubacteria and salvaged by eukaryotes for incorporation into tRNA. Q34 modification stimulates Dnmt2/Pmt1-dependent C38 methylation (m5C38) in the tRNAAsp anticodon loop in Schizosaccharomyces pombe. Here, we show by ribosome profiling in S.

The interplay of epigenetic marks during stem cell differentiation and development.

Chromatin, the template for epigenetic regulation, is a highly dynamic entity that is constantly reshaped during early development and differentiation. Epigenetic modification of chromatin provides the necessary plasticity for cells to respond to environmental and positional cues, and enables the maintenance of acquired information without changing the DNA sequence. The mechanisms involve, among others, chemical modifications of chromatin, changes in chromatin constituents and reconfiguration of chromatin interactions and 3D structure.

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2.

Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb).

The role of S100a4 (Mts1) in Apc- and Smad4-driven tumour onset and progression.

Introduction: S100a4 is a calcium-binding protein belonging to the family of S100-proteins, highly expressed in different stromal cell types. S100A4 has been reported as a prognostic marker in colorectal cancer in association with tumour progression and metastasis.

Methods: In this study, we analysed the in vivo role of S100a4 in intestinal tumour initiation and progression using different transgenic and knockout mouse models.

Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2.

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68).

Dynamic Reorganization of Extremely Long-Range Promoter-Promoter Interactions between Two States of Pluripotency.

Serum-to-2i interconversion of mouse embryonic stem cells (mESCs) is a valuable in vitro model for early embryonic development. To assess whether 3D chromatin organization changes during this transition, we established Capture Hi-C with target-sequence enrichment of DNase I hypersensitive sites. We detected extremely long-range intra- and inter-chromosomal interactions between a small subset of H3K27me3 marked bivalent promoters involving the Hox clusters in serum-grown cells.

Cancer stem cells, pluripotency, and cellular heterogeneity: a WNTer perspective.

Cancer stem cells (CSCs) are thought to represent the "beating heart" of malignant growth as they continuously fuel tumors through their ability to self-renew and differentiate. Moreover, they are also believed to underlie malignant behavior, local invasion, and metastasis in distal organ sites upon reversible epithelial-to-mesenchymal transitions (EMTs). Nevertheless, the CSC concept has been the object of controversy, mainly due to the absence of robust operational definitions and to the lack of consistency in the use of the often incorrect nomenclature employed to refer to these cells.

Cancer stemness in Apc- vs. Apc/KRAS-driven intestinal tumorigenesis.

Constitutive activation of the Wnt pathway leads to adenoma formation, an obligatory step towards intestinal cancer. In view of the established role of Wnt in regulating stemness, we attempted the isolation of cancer stem cells (CSCs) from Apc- and Apc/KRAS-mutant intestinal tumours. Whereas CSCs are present in Apc/KRAS tumours, they appear to be very rare (<10(-6)) in the Apc-mutant adenomas.