The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.

During persistent antigen stimulation, exhausted CD8 T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8 T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway.

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.

Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche.

Ascorbate depletion increases quiescence and self-renewal potential in hematopoietic stem cells and multipotent progenitors.

Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter severely depleted ascorbate from hematopoietic cells.

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.

Unlabelled: Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction ( ). Autophagy is central for the benefits associated with activation of longevity signaling programs ( ), and for HSC function and response to nutrient stress ( ). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional ( ).

Metabolic regulation of somatic stem cells in vivo.

Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function.

BMAL1 drives muscle repair through control of hypoxic NAD regeneration in satellite cells.

The process of tissue regeneration occurs in a developmentally timed manner, yet the role of circadian timing is not understood. Here, we identify a role for the adult muscle stem cell (MuSC)-autonomous clock in the control of muscle regeneration following acute ischemic injury. We observed greater muscle repair capacity following injury during the active/wake period as compared with the inactive/rest period in mice, and loss of within MuSCs leads to impaired muscle regeneration.

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues.

Little is known about the metabolic regulation of rare cell populations because most metabolites are hard to detect in small numbers of cells. We previously described a method for metabolomic profiling of flow cytometrically isolated hematopoietic stem cells (HSCs) that detects 60 metabolites in 10,000 cells (Agathocleous et al., 2017).

GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells.

The master regulatory transcription factor GATA-2 triggers hematopoietic stem and progenitor cell generation. GATA2 haploinsufficiency is implicated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and GATA2 overexpression portends a poor prognosis for AML. However, the constituents of the GATA-2-dependent genetic network mediating pathogenesis are unknown.

Navigating Transcriptional Coregulator Ensembles to Establish Genetic Networks: A GATA Factor Perspective.

Complex developmental programs require orchestration of intrinsic and extrinsic signals to control cell proliferation, differentiation, and survival. Master regulatory transcription factors are vital components of the machinery that transduce these stimuli into cellular responses. This is exemplified by the GATA family of transcription factors that establish cell type-specific genetic networks and control the development and homeostasis of systems including blood, vascular, adipose, and cardiac.

Epigenetic Determinants of Erythropoiesis: Role of the Histone Methyltransferase SetD8 in Promoting Erythroid Cell Maturation and Survival.

Erythropoiesis, in which committed progenitor cells generate millions of erythrocytes daily, involves dramatic changes in the chromatin structure and transcriptome of erythroblasts, prior to their enucleation. While the involvement of the master-regulatory transcription factors GATA binding protein 1 (GATA-1) and GATA-2 in this process is established, the mechanistic contributions of many chromatin-modifying/remodeling enzymes in red cell biology remain enigmatic. We demonstrated that SetD8, a histone methyltransferase that catalyzes monomethylation of histone H4 at lysine 20 (H4K20me1), is a context-dependent GATA-1 corepressor in erythroid cells.

The exosome complex establishes a barricade to erythroid maturation.

Complex genetic networks control hematopoietic stem cell differentiation into progenitors that give rise to billions of erythrocytes daily. Previously, we described a role for the master regulator of erythropoiesis, GATA-1, in inducing genes encoding components of the autophagy machinery. In this context, the Forkhead transcription factor, Foxo3, amplified GATA-1-mediated transcriptional activation.

Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points.

Hematopoiesis is an exquisitely regulated process in which stem cells in the developing embryo and the adult generate progenitor cells that give rise to all blood lineages. Master regulatory transcription factors control hematopoiesis by integrating signals from the microenvironment and dynamically establishing and maintaining genetic networks. One of the most rudimentary aspects of cell type-specific transcription factor function, how they occupy a highly restricted cohort of cis-elements in chromatin, remains poorly understood.

Establishing a hematopoietic genetic network through locus-specific integration of chromatin regulators.

The establishment and maintenance of cell type-specific transcriptional programs require an ensemble of broadly expressed chromatin remodeling and modifying enzymes. Many questions remain unanswered regarding the contributions of these enzymes to specialized genetic networks that control critical processes, such as lineage commitment and cellular differentiation. We have been addressing this problem in the context of erythrocyte development driven by the transcription factor GATA-1 and its coregulator Friend of GATA-1 (FOG-1).

Transcriptional mechanisms underlying hemoglobin synthesis.

The physiological switch in expression of the embryonic, fetal, and adult β-like globin genes has garnered enormous attention from investigators interested in transcriptional mechanisms and the molecular basis of hemoglobinopathies. These efforts have led to the discovery of cell type-specific transcription factors, unprecedented mechanisms of transcriptional coregulator function, genome biology principles, unique contributions of nuclear organization to transcription and cell function, and promising therapeutic targets. Given the vast literature accrued on this topic, this article will focus on the master regulator of erythroid cell development and function GATA-1, its associated proteins, and its frontline role in controlling hemoglobin synthesis.

Results of the 2009 National Resident Matching Program: family medicine.

The results of the 2009 National Resident Matching Program (NRMP) reflect a persistently low level of student interest in family medicine residency training in the United States. Compared with the 2008 Match, 70 fewer positions (with 89 fewer US seniors) were filled in family medicine residency programs through the NRMP in 2009, at the same time that 18 fewer positions were filled in primary care internal medicine (11 fewer US seniors), one more position was filled in pediatrics-primary care (three more US seniors), and 13 more positions were filled in internal medicine-pediatrics programs (but with seven fewer US seniors). Multiple forces, including student perspectives of the demands, rewards and prestige of the specialty, the turbulence and uncertainty of the health care and economic environments, lifestyle issues, the advice of deans, and the impact of faculty role models, continue to influence medical student career choices.

Entry of US medical school graduates into family medicine residencies: 2008-2009 and 3-year summary.

This is the 28th report prepared by the American Academy of Family Physicians (AAFP) on the percentage of each US medical school's graduates entering family medicine residency programs. Approximately 8.2% of the 16,336 graduates of US medical schools between July 2007 and June 2008 were first-year family medicine residents in 2008, compared with 8.

Results of the 2008 National Resident Matching Program: family medicine.

The results of the 2008 National Resident Matching Program (NRMP) reflect a currently stable level of student interest in family medicine residency training in the United States. Compared with the 2007 Match, 91 more positions (with 65 more US seniors) were filled in family medicine residency programs through the NRMP in 2008, at the same time as 10 fewer (one fewer US senior) in primary care internal medicine, eight fewer positions were filled in pediatrics-primary care (10 fewer US seniors), and 19 fewer (27 fewer US seniors) in internal medicine-pediatrics programs. Multiple forces, including student perspectives of the demands, rewards, and prestige of the specialty, the turbulence and uncertainty of the health care environment, lifestyle issues, and the impact of faculty role models, continue to influence medical student career choices.

Entry of US medical school graduates into family medicine residencies: 2007-2008 and 3-year summary.

This is the 27th report prepared by the American Academy of Family Physicians (AAFP) on the percentage of each US medical school's graduates entering family medicine residency programs. Approximately 8.3% of the 16,300 graduates of US medical schools between July 2006 and June 2007 were first-year family medicine residents in 2007, compared with 8.

Results of the 2007 National Resident Matching Program: family medicine.

The results of the 2007 National Resident Matching Program (NRMP) reflect a currently stable level of student interest in family medicine residency training in the United States. Compared with the 2006 Match, five fewer positions (with 25 fewer US seniors) were filled in family medicine residency programs through the NRMP in 2007, at the same time as 20 fewer (two more US seniors) in primary care internal medicine, the same number of pediatrics-primary care (four fewer US seniors), and one more (19 fewer US seniors) in internal medicine-pediatrics programs. Multiple forces, including student perspectives of the demands, rewards, and prestige of the specialty; the turbulence and uncertainty of the health care environment; lifestyle issues; and the impact of faculty role models continue to influence medical student career choices.