Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis

Summary Insulin resistance is a sine qua non of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, aging, and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumor necrosis factor-α (TNF) or by the steroid dexamethasone (Dex) to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms

Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants

Summary Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. We find that ~90% of causal variants are noncoding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10–20% directly alter recognizable transcription factor binding motifs. Rather, most noncoding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models

Comparative Differentiation of Bone Marrow, Umbilical Cord Blood and Skin Derived Cells

We analyzed the ability of bone marrow-derived stem cells, umbilical cord blood-derived stem cells, quiescent, and FGF-2 stimulated adult human dermal fibroblasts to differentiate into the three main lineages. Histochemical and immunocytochemistry assays were performed on the cell cultures to determine the success of specific differentiation protocols. The data showed that all treatments except the umbilical cord blood-derived stem cells differentiated into the adipogenic lineage, although none of the treatments successfully differentiated into the chondrogenic or osteogenic lineages. The purpose of this project was to develop in vitro assays with which to measure success of future de-differentiation experiments

Stem Cells and Society

The purpose of this IQP is to examine the different types of stem cells, the sources from which they are isolated, their current applications, and the ethical and legal issues that scientists face while trying to conduct their research. Currently the average person often errantly believes that stem cell research only involves the destruction of embryos, when there are many different types of stem cells used in research. We aim for this report to excite people into seeking greater understanding of stem cell research

Genetic and epigenetic fine mapping of causal autoimmune disease variants.

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models

Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’1–3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1− tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions

Publisher Correction : Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors (Nature Medicine, (2019), 25, 8, (1260-1265), 10.1038/s41591-019-0493-4)

In the version of this article initially published, a numbering error mistakenly associated author Paloma Cejas with affiliation 15, Hebrew University; the affiliation footnote has been removed. Affiliations 10 (published as Massachusetts General Hospital and Harvard Medical School) and 11 (published as UMC Utrecht Cancer Center) were incorrectly transposed, affecting authors Menno R. Vriens, and Carlos Fernandez-del Castillo and Christina R. Ferrone, respectively. In Figure 2a, the image was misoriented by 90°, resulting in incorrect orientation of the dendrogram. The errors have been corrected in the HTML and PDF versions of the article