More to cohesin than meets the eye: complex diversity for fine-tuning of function

Recent years have witnessed a dramatic expansion in our understanding of gene control. It is now widely appreciated that the spatial organization of the genome and the manner in which genes and regulatory elements are embedded therein has a critical role in facilitating the regulation of gene expression. The loop structures that underlie chromosome organization are anchored by cohesin complexes. Several components of the cohesin complex have multiple paralogs, leading to different levels of cohesin complex variants in cells. Here we review the current literature around cohesin variants and their known functions. We further discuss how variation in cohesin complex composition can result in functional differences that can impact genome organization and determine cell fate

Association of change in daily step count over five years with insulin sensitivity and adiposity: population based cohort study

addresses: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne 3052, Australia. [email protected]: Journal Article; Research Support, Non-U.S. Gov'tCopyright © 2011 by the BMJ Publishing Group Ltd. This articles was first published in: BMJ, 2011, Vol. 342, pp. c7249 -To investigate the association between change in daily step count and both adiposity and insulin sensitivity and the extent to which the association between change in daily step count and insulin sensitivity may be mediated by adiposity

Objectively Measured Physical Activity and the Subsequent Risk of Incident Dysglycemia: The Australian Diabetes, Obesity and Lifestyle Study (AusDiab)

OBJECTIVE - To investigate pedometer-measured physical activity (PA) in 2000 and change in PA over 5 years with subsequent risk of dysglycemia by 2005. RESEARCH DESIGN AND METHODS - This prospective cohort study in Tasmania, Australia, analyzed 458 adults with normal glucose tolerance and a mean (SD) age of 49.7 (12.1) years in 2000. Variables assessed in 2000 and 2005 included PA, by pedometer and questionnaire, nutrient intake, and other lifestyle factors. Incident dysglycemia was defined as the development of impaired fasting glucose or impaired glucose tolerance revealed by oral glucose tolerance testing in 2005, without type 2 diabetes. RESULTS - Incident dysglycemia developed in 26 participants during the 5-year period. Higher daily steps in 2000 were independently associated with a lower 5-year risk of incident dysglycemia (adjusted odds ratio [AOR] 0.87 [95% CI 0.77-0.97] per 1,000-step increment). Higher daily steps in 2005, after controlling for baseline steps in 2000 (thus reflecting change in steps over 5 years), were not associated with incident dysglycemia (AOR 1.02 [0.92-1.14]). Higher daily steps in 2000 were also associated with lower fasting blood glucose, but not 2-h plasma glucose by 2005. Further adjustment for BMI or waist circumference did not remove these associations. CONCLUSIONS - Among community-dwelling adults, a higher rate of daily steps is associated with a reduced risk of incident dysglycemia. This effect appears to be not fully mediated through reduced adiposity

The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)

The N-terminus of Stag1 is required to repress the 2C program by maintaining rRNA expression and nucleolar integrity.

Our understanding of how STAG proteins contribute to cell identity and disease have largely been studied from the perspective of chromosome topology and protein-coding gene expression. Here, we show that STAG1 is the dominant paralog in mouse embryonic stem cells (mESCs) and is required for pluripotency. mESCs express a wide diversity of naturally occurring Stag1 isoforms, resulting in complex regulation of both the levels of STAG paralogs and the proportion of their unique terminal ends. Skewing the balance of these isoforms impacts cell identity. We define a novel role for STAG1, in particular its N-terminus, in regulating repeat expression, nucleolar integrity, and repression of the two-cell (2C) state to maintain mESC identity. Our results move beyond protein-coding gene regulation via chromatin loops to new roles for STAG1 in nucleolar structure and function, and offer fresh perspectives on how STAG proteins, known to be cancer targets, contribute to cell identity and disease