Critical evaluation of transcription factor Atf2 as a candidate modulator of alcohol preference in mouse and human populations

Genome-wide association studies (GWAS) to date have discovered thousands of genetic variants linked to human diseases and traits, which hold the potential to unravel the mechanisms of complex phenotypes. However, given that the majority of these associated variants reside in non-coding genomic regions, their predicted cis and trans-regulatory functions remain largely undefined. Here we show that correlation between human diseases and traits can follow geographical distribution of human populations, and that the underlying mechanism is at least partly genetically based. We report two Type 2 Diabetes (T2D) GWAS variants (rs7903146 and rs12255372) in the TCF7L2 locus that regulate expression in skin tissues but not lymphoblastoid or adipose tissues, of the KITLG gene that encodes an important regulator of melanogenesis and light hair color in European populations. We also report extensive binding events of TCF7L2 protein in the promoter region, immediate upstream region and first intron of the KITLG gene, which supports a trans-interaction between TCF7L2 and KITLG. We further show that both light hair color and T2D genetic variants are correlated with geographic latitude. Taken together, our observations suggest that natural variation in transcription factor loci in European human populations may be an underlying and confounding factor for the geographical correlation between human phenotypes, such as type 2 diabetes and light hair color. We postulate that transcription factor regulation may confound the correlation between seemingly diverse human traits. Furthermore, our findings demonstrate the importance of dissecting the genomic architecture of GWAS loci using multiple genetic and genomic datasets.

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The Archaeology of Population Dynamics

Current Swedish Archaeology ◽

10.37718/csa.2019.02 ◽

2019 ◽

Vol 27 (27) ◽

pp. 37-51

Author(s):

John Barrett

Keyword(s):

Population Dynamics ◽

Critical Evaluation ◽

Human Populations ◽

Southwest Asia ◽

Recent Interpretation

A critical evaluation of the recent interpretation of aDNA data that link the adoption of domesticated plants and animals across Europe with a migration of human populations from southwest Asia and the Aegean. These data have been used to question previous models that argued for the uptake of farming by indigenous hunter-gatherer populations.

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ATAC-Seq Reveals an Isl1 Enhancer That Regulates Sinoatrial Node Development and Function

Circulation Research ◽

10.1161/circresaha.120.317145 ◽

2020 ◽

Vol 127 (12) ◽

pp. 1502-1518

Author(s):

Giselle Galang ◽

Ravi Mandla ◽

Hongmei Ruan ◽

Catherine Jung ◽

Tanvi Sinha ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Transcription Factor ◽

Sinoatrial Node ◽

Regulatory Elements ◽

Right Atrial ◽

Specific Gene ◽

Human Populations ◽

And Function ◽

Accessible Chromatin

Rationale: Cardiac pacemaker cells (PCs) in the sinoatrial node (SAN) have a distinct gene expression program that allows them to fire automatically and initiate the heartbeat. Although critical SAN transcription factors, including Isl1 (Islet-1), Tbx3 (T-box transcription factor 3), and Shox2 (short-stature homeobox protein 2), have been identified, the cis -regulatory architecture that governs PC-specific gene expression is not understood, and discrete enhancers required for gene regulation in the SAN have not been identified. Objective: To define the epigenetic profile of PCs using comparative ATAC-seq (assay for transposase-accessible chromatin with sequencing) and to identify novel enhancers involved in SAN gene regulation, development, and function. Methods and Results: We used ATAC-seq on sorted neonatal mouse SAN to compare regions of accessible chromatin in PCs and right atrial cardiomyocytes. PC-enriched assay for transposase-accessible chromatin peaks, representing candidate SAN regulatory elements, were located near established SAN genes and were enriched for distinct sets of TF (transcription factor) binding sites. Among several novel SAN enhancers that were experimentally validated using transgenic mice, we identified a 2.9-kb regulatory element at the Isl1 locus that was active specifically in the cardiac inflow at embryonic day 8.5 and throughout later SAN development and maturation. Deletion of this enhancer from the genome of mice resulted in SAN hypoplasia and sinus arrhythmias. The mouse SAN enhancer also directed reporter activity to the inflow tract in developing zebrafish hearts, demonstrating deep conservation of its upstream regulatory network. Finally, single nucleotide polymorphisms in the human genome that occur near the region syntenic to the mouse enhancer exhibit significant associations with resting heart rate in human populations. Conclusions: (1) PCs have distinct regions of accessible chromatin that correlate with their gene expression profile and contain novel SAN enhancers, (2) cis -regulation of Isl1 specifically in the SAN depends upon a conserved SAN enhancer that regulates PC development and SAN function, and (3) a corresponding human ISL1 enhancer may regulate human SAN function.

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Global, cell non-autonomous gene regulation drives individual lifespan among isogenic C. elegans

eLife ◽

10.7554/elife.65026 ◽

2021 ◽

Vol 10 ◽

Author(s):

Holly E Kinser ◽

Matthew C Mosley ◽

Isaac B Plutzer ◽

Zachary Pincus

Keyword(s):

Transcription Factor ◽

Transgene Expression ◽

Predictive Ability ◽

Human Populations ◽

C Elegans ◽

Regulatory Processes ◽

Gene Regulatory ◽

Lifespan Variability ◽

The Relationship ◽

Species Lifespan

Across species, lifespan is highly variable among individuals within a population. Even genetically identical Caenorhabditis elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoter::GFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long- vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual’s lifespan.

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The sense of obligation is culturally modulated

Behavioral and Brain Sciences ◽

10.1017/s0140525x19002371 ◽

2020 ◽

Vol 43 ◽

Author(s):

Andrea Bender

Keyword(s):

Cultural Studies ◽

Cross Cultural ◽

Human Populations ◽

Cultural Group ◽

Target Article ◽

Sense Of Obligation ◽

Cross Cultural Studies

Abstract Tomasello argues in the target article that, in generalizing the concrete obligations originating from interdependent collaboration to one's entire cultural group, humans become “ultra-cooperators.” But are all human populations cooperative in similar ways? Based on cross-cultural studies and my own fieldwork in Polynesia, I argue that cooperation varies along several dimensions, and that the underlying sense of obligation is culturally modulated.

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Author response for "Identification of Retinal Ganglion Cell Types and Brain Nuclei expressing the transcription factor Brn3c/Pou4f3 using a Cre recombinase knock‐in allele"

10.1002/cne.25065/v2/response1 ◽

2020 ◽

Author(s):

Nadia Parmhans ◽

Anne Drury Fuller ◽

Eileen Nguyen ◽

Katherine Chuang ◽

David Swygart ◽

...

Keyword(s):

Transcription Factor ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Cell Types ◽

Cre Recombinase ◽

Author Response ◽

Retinal Ganglion ◽

Brain Nuclei

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Electron Microscopy of Metal-Matrix Composites

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100069016 ◽

1970 ◽

Vol 28 ◽

pp. 404-405

Author(s):

A. Lawley ◽

M. R. Pinnel ◽

A. Pattnaik

Keyword(s):

Electron Microscopy ◽

Metal Matrix Composites ◽

Metal Matrix ◽

Critical Evaluation ◽

Elastic Behavior ◽

Matrix Composites ◽

Directionally Solidified ◽

Fracture Characteristics ◽

Broad Program

As part of a broad program on composite materials, the role of the interface on the micromechanics of deformation of metal-matrix composites is being studied. The approach is to correlate elastic behavior, micro and macroyielding, flow, and fracture behavior with associated structural detail (dislocation substructure, fracture characteristics) and stress-state. This provides an understanding of the mode of deformation from an atomistic viewpoint; a critical evaluation can then be made of existing models of composite behavior based on continuum mechanics. This paper covers the electron microscopy (transmission, fractography, scanning microscopy) of two distinct forms of composite material: conventional fiber-reinforced (aluminum-stainless steel) and directionally solidified eutectic alloys (aluminum-copper). In the former, the interface is in the form of a compound and/or solid solution whereas in directionally solidified alloys, the interface consists of a precise crystallographic boundary between the two constituents of the eutectic.

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Transcription factor/DNA interactions visualized by electron spectroscopic imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100122654 ◽

1992 ◽

Vol 50 (1) ◽

pp. 450-451

Author(s):

David P. Bazett-Jones ◽

Mark L. Brown

Keyword(s):

Transcription Factor ◽

Dna Sequences ◽

Transcription Initiation ◽

Molecular Mechanisms ◽

Phosphorus Content ◽

Spectroscopic Imaging ◽

Electron Spectroscopic Imaging ◽

Dna Backbone ◽

Two Parameters ◽

High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

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