A congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1

Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation

Lipoprotein (a) and stroke

Strokes are one of the most common causes of mortality and long term severe disability. There is evidence that lipoprotein (a) (Lp(a)) is a predictor of many forms of vascular disease, including premature coronary artery disease. Several studies have also evaluated the association between Lp(a) and ischaemic (thrombotic) stroke. Several cross sectional (and a few prospective) studies provide contradictory findings regarding Lp(a) as a predictor of ischaemic stroke. Several factors might contribute to the existing confusion—for example, small sample sizes, different ethnic groups, the influence of oestrogens in women participating in the studies, plasma storage before Lp(a) determination, statistical errors, and selection bias. This review focuses on the Lp(a) related mechanisms that might contribute to the pathogenesis of ischaemic stroke. The association between Lp(a) and other cardiovascular risk factors is discussed. Therapeutic interventions that can lower the circulating concentrations of Lp(a) and thus possibly reduce the risk of stroke are also considered. Key Words: atherothrombosis • fibrinogen • homocysteine • lipids • lipoprotein a • strok