ABSTRACT
B cell CLL/lymphoma 11A (BCL11A) is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs) remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6), and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A.
Subject(s)
Carrier Proteins/genetics , Cellular Senescence/genetics , Hematopoiesis/genetics , Hematopoietic Stem Cells/pathology , Nuclear Proteins/genetics , Animals , Cyclin-Dependent Kinase 6/biosynthesis , DNA-Binding Proteins , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Repressor ProteinsABSTRACT
This article reports a case study of the legislative and media discourse surrounding the addition of sexual orientation and gender identity language to the employment nondiscrimination ordinance of a city in the heart of the Bible Belt. The purpose of the study is to uncover how different identities were constructed and contested at city council meetings and in the news media on the way to passing legal protection for LGBT city employees in a region that is often characterized by anti-gay prejudice. This debate over the nondiscrimination ordinance centered on the question of whether LGBT identities are equivalent to identity categories based on race, gender, or religious belief, and it was shaped by various intergroup communication dynamics, specifically between members of the LGBT minority and the straight majority, between LGBT and Christian identities, and between "true" and "false" Christian identities.
