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The differentiation of self-renewing progenitor cells requires not only the regulation of lineage- and developmental stage-specific genes but also the coordinated adaptation of housekeeping functions from a metabolically active, proliferative state toward quiescence. How metabolic and cell-cycle states are coordinated with the regulation of cell type-specific genes is an important question, because dissociation between differentiation, cell cycle, and metabolic states is a hallmark of cancer. Here, we use a model system to systematically identify key transcriptional regulators of Ikaros-dependent B cell-progenitor differentiation. We find that the coordinated regulation of housekeeping functions and tissue-specific gene expression requires a feedforward circuit whereby Ikaros down-regulates the expression of Myc. Our findings show how coordination between differentiation and housekeeping states can be achieved by interconnected regulators. Similar principles likely coordinate differentiation and housekeeping functions during progenitor cell differentiation in other cell lineages.

Objective: The aim of this study was to investigate whether a shared genetic susceptibility exists between individuals with rheumatoid arthritis (RA) and individuals with myocardial infarction (MI)—including major MI risk factors—and to quantify the degree of any such overlap. Methods: Genome‐wide association study (GWAS) data for individuals with RA were constructed from a sample of 26,637 Swedish patients with RA and controls without RA. For patients with MI, GWAS data were obtained from a previously published meta‐analysis. Genome‐wide genetic correlation was estimated via linkage disequilibrium score regression. LAVA was employed to estimate local genetic correlations in ~2,500 nonoverlapping loci, including the major histocompatibility complex. The controls without RA were used for reference panel data. We also assessed stratified estimates of both genome‐wide and local genetic correlation based on subsamples of individuals with seropositive RA and those with seronegative RA. Furthermore, genome‐wide genetic correlation was estimated between RA and selected cardiovascular risk factors to elucidate pleiotropic relationships. Results: Following quality control, our GWAS of patients with RA consisted of 25,826 individuas. Genome‐wide genetic correlation between patients with RA and MI was estimated to 0.13 (95% confidence interval –0.03 to 0.29). Six regions exhibited significant local genetic correlation, though none harbored any known risk single‐nucleotide polymorphisms for either of the two traits. Estimates were similar in both individuals with seropositive RA and those with seronegative RA. No statistically significant genetic correlations were observed between RA risk factors and any of the MI risk factors. Conclusion: Our findings indicate that genetic overlap between patients with RA and MI is minor. Furthermore, genetic overlap between RA and MI risk factors seem unlikely to provide a major contribution to the increased risk of MI observed in patients with RA. [ABSTRACT FROM AUTHOR]

Objectives To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. Methods We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short- and long-term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. Results No individual SNP reached genome-wide significance (P  < 5 × 10−8), either for persistence at 1 year or at 3 years. The RA PRS was not significantly associated with MTX treatment persistence at 1 year [relative risk (RR) = 0.98 (0.96–1.01)] or at 3 years [RR = 0.96 (0.93–1.00)]. The heritability of MTX treatment persistence was estimated to be 0.45 (0.15–0.75) at 1 year and 0.14 (0–0.40) at 3 years. The results in seropositive RA were comparable with those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. Conclusion Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, MTX monotherapy persistence was lower in patients with a greater genetic disposition, per the PRS, towards RA. [ABSTRACT FROM AUTHOR]

To understand the interface between global brain function and molecular neuroscience--that is, the microcircuit level--a major challenge. Such understanding is prerequisite if we are to account for neural function in cellular terms. Very few vertebrate microcircuits are yet understood because their analysis is demanding technically. In this review of the TINS Microcircuits Special Feature, we attempt to shed light on the problem by comparing the operation of four types of microcircuit, to identify common molecular and cellular components. Central pattern generator (CPG) networks underlying rhythmic movements and hippo-campal microcircuits that generate gamma and theta rhythms are compared with the neocortical microcircuits used in cognitive tasks and a cerebellar network. The long-term goal is to identify the components of a molecular and synaptic tool kit for the design of different microcircuits.