Implications of noncoding regulatory functions in the development of insulinomas.

Insulinomas are rare neuroendocrine tumors arising from pancreatic ß cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in ß cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of ß cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.

MacroH2As regulate enhancer-promoter contacts affecting enhancer activity and sensitivity to inflammatory cytokines.

MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment.

Topology detection in cavity QED.

We explore the physics of topological lattice models immersed in c-QED architectures for arbitrary coupling strength with the photon field. We propose the use of the cavity transmission as a topological marker and study its behaviour. For this, we develop an approach combining the input-output formalism with a Mean-Field plus fluctuations description of the setup. We illustrate our results with the specific case of a fermionic Su-Schrieffer-Heeger (SSH) chain coupled to a single-mode cavity. Our findings confirm that the cavity can indeed act as a quantum sensor for topological phases, where the initial state preparation plays a crucial role. Additionally, we discuss the persistence of topological features when the coupling strength increases, in terms of an effective Hamiltonian, and calculate the entanglement entropy. Our approach can be applied to other fermionic systems, opening a route to the characterization of their topological properties in terms of experimental observables.

The ß-Cell Genomic Landscape in T1D: Implications for Disease Pathogenesis.

PURPOSE OF REVIEW: Type 1 diabetes (T1D) develops as a consequence of a combination of genetic predisposition and environmental factors. Combined, these events trigger an autoimmune disease that results in progressive loss of pancreatic ß cells, leading to insulin deficiency. This article reviews the current knowledge on the genetics of T1D with a specific focus on genetic variation in pancreatic islet regulatory networks and its implication to T1D risk and disease development. RECENT FINDINGS: Accumulating evidence suggest an active role of ß cells in T1D pathogenesis. Based on such observation several studies aimed in mapping T1D risk variants acting at the ß cell level. Such studies unravel T1D risk loci shared with type 2 diabetes (T2D) and T1D risk variants potentially interfering with ß-cell responses to external stimuli. The characterization of regulatory genomics maps of disease-relevant states and cell types can be used to elucidate the mechanistic role of ß cells in the pathogenesis of T1D.

Simulation of 1D Topological Phases in Driven Quantum Dot Arrays.

We propose a driving protocol which allows us to use quantum dot arrays as quantum simulators for 1D topological phases. We show that by driving the system out of equilibrium, one can imprint bond order in the lattice (producing structures such as dimers, trimers, etc.) and selectively modify the hopping amplitudes at will. Our driving protocol also allows for the simultaneous suppression of all the undesired hopping processes and the enhancement of the necessary ones, enforcing certain key symmetries which provide topological protection. In addition, we have discussed its implementation in a 12-QD array with two interacting electrons and found correlation effects in their dynamics, when configurations with different number of edge states are considered.

DNA methylation in thyroid cancer.

In recent years, cancer genomics has provided new insights into genetic alterations and signaling pathways involved in thyroid cancer. However, the picture of the molecular landscape is not yet complete. DNA methylation, the most widely studied epigenetic mechanism, is altered in thyroid cancer. Recent technological advances have allowed the identification of novel differentially methylated regions, methylation signatures and potential biomarkers. However, despite recent progress in cataloging methylation alterations in thyroid cancer, many questions remain unanswered. The aim of this review is to comprehensively examine the current knowledge on DNA methylation in thyroid cancer and discuss its potential clinical applications. After providing a general overview of DNA methylation and its dysregulation in cancer, we carefully describe the aberrant methylation changes in thyroid cancer and relate them to methylation patterns, global hypomethylation and gene-specific alterations. We hope this review helps to accelerate the use of the diagnostic, prognostic and therapeutic potential of DNA methylation for the benefit of thyroid cancer patients.