Faculty Opinions recommendation of A critical role for TCF-1 in T-lineage specification and differentiation.

Abstract CCAAT/ enhancer binding protein α (C/EBP α) is a member of the bZIP family of transcription factors that plays a critical role for early myeloid differentiation. C/EBP α knockout mice showed a complete differentiation block at myeloblast stage in hematopoietic system, and mature neutrophils and eosinophils are absent in the peripheral blood. Lineage specification in developmental tree of hematopoiesis is generally determined by a lineage specific transcription factors such as C/EBP α and GATA-1 that allow commitment to the specific lineage with simultaneous extinction of their capacity to differentiate into the other ones. However, recent evidences shown by the ectopic expression of above transcription factors unveiled the unexpected developmental plasticity of various progenitors such as MEP (erythroid/ megakaryocyte progenitor) and CLP (common lymphoid progenitor). GATA-1 is reported to convert CLP and CMP (common myeloid progenitor) into erythroid/ megakaryocyte lineage, however, the effect of C/EBP α on MEP and CLP is still unlcear. In order to investigate the role of C/EBP α in the various aspect of hematopoietic differentiation, especially its effect on the lineage specification at different stages of differentiation in vivo, we generated transgenic mice expressing inducible form of C/EBP α (C/EBP α-ER) under H-2K promoter (C/EBP α-ER Tg). In these mice, C/EBP α activity can be induced conditionally by 4-hydroxy tamoxifen (4-HT) in all hematopoietic cells. As expected, C/EBP α-ER was expressed in almost all hematopoietic tissues including bone marrow, spleen and thymus in these mice. Gel shift analysis revealed that C/EBP α-ER was activated by 4-HT, and showed specific binding to C/EBP-specific oligonucleotide in these tissues. Next we tested differentiation plasticity of erythroid and lymphoid progenitors by ectopically inducing C/EBP α-ER activity in these cells. We sorted MEP and CLP by FACS from C/EBP α-ER Tg and examined their clonogenic activities in the presence or absence of 4-HT. In the absence of 4-HT, MEP and CLP exclusively formed erythroid/ megakaryocyte and lymphoid colonies, respectively, as previously reported. Surprisingly however, these cells dramatically changed their fate of differentiation and formed significant numbers of granulocyte/ macrophage (GM) colonies in the presence of 4-HT, indicating that ectopic activation of C/EBP α-ER activity skewed their differentiation pathways to myeloid lineage. Cytospin preparation of the colonies and RT-PCR analysis revealed that these were accompanied by the morphological differentiation to granulocytes/ macrophages, and upregulation of myeloid-specific genes at mRNA level. These results indicate that MEP and CLP are not fully committed to either erythroid/ megakaryocyte or lymphoid lineage, and possess differentiation plasticity that can be redirected to myeloid lineage.

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Abstract MP245: Tet Proteins Regulate Second Heart Field Multipotent Progenitors Differentiating To Myocytes

Circulation Research ◽

10.1161/res.129.suppl_1.mp245 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Shaohai Fang ◽

Jia Li ◽

Jeff D Steimle ◽

Lei Guo ◽

Yuhan Yang ◽

...

Keyword(s):

Dna Methylation ◽

Heart Development ◽

Cardiac Development ◽

Critical Role ◽

Dna Demethylation ◽

Lineage Specification ◽

Second Heart Field ◽

Heart Field ◽

Cardiac Lineage ◽

Tet Protein

DNA methylation and demethylation play an important role in shaping the epigenetic landscape and chromatin accessibility to control gene expression during development in mammals. Ten-eleven Translocation (Tet1, Tet2 and Tet3) is a family of dioxygenases that catalyze DNA methylation oxidation with ultimate DNA demethylation. Our previous study showed that cardiac-specific deletion of Tet2 and Tet3 could disrupt YY1-mediated long range chromatin interactions during heart development and lead to ventricular non-compaction cardiomyopathy. However, it is still unclear whether and how Tet protein mediated epigenetic modifications contribute to cardiac lineage specification during embryonic development. In this study, we generated cardiac specific Tet1-3 triple deficient (Tet-TKO) mouse lines using various cardiac specific Cres to evaluate the function of Tet protein in regulating cardiac lineage specification. We observed developmental defects at outflow tract (OFT) in Tet-TKO embryos, suggesting that Tet deficiency affects the second heart field (SHF) development. Single cell RNA-seq analysis further revealed the accumulation of multipotent SHF progenitors and subsequent halt of myocyte differentiation upon Tet depletion. At the molecular level, we found that Tet ablation perturbs the transcriptional network of Islet1, a transcription factor that is crucial for cardiac development in embryos. Overall, our study demonstrates a critical role of Tet-mediated epigenetic regulation for embryonic cardiac development.

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Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism

Nuclear Receptor Signaling ◽

10.1621/nrs.07003 ◽

2009 ◽

Vol 7 (1) ◽

pp. nrs.07003 ◽

Cited By ~ 367

Author(s):

Anton M. Jetten

Keyword(s):

Circadian Clock ◽

Energy Homeostasis ◽

Potential Role ◽

Target Genes ◽

Critical Role ◽

Lymphoid Tissues ◽

Rhythmic Pattern ◽

Lineage Specification ◽

Orphan Receptors ◽

Physiological Processes

The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORα, -β, and -γ (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORa plays a critical role in the development of the cerebellum, that both RORα and RORβ are required for the maturation of photoreceptors in the retina, and that RORγ is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORγ in lineage specification of uncommitted CD4+T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors.

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The epigenetic control of stemness in CD8+T cell fate commitment

Science ◽

10.1126/science.aah6499 ◽

2018 ◽

Vol 359 (6372) ◽

pp. 177-186 ◽

Cited By ~ 65

Author(s):

Luigia Pace ◽

Christel Goudot ◽

Elina Zueva ◽

Paul Gueguen ◽

Nina Burgdorf ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Fate ◽

Critical Role ◽

Long Term Memory ◽

Lineage Specification ◽

Control Of Gene Expression ◽

Effector Cells ◽

Chromatin Dynamics

After priming, naïve CD8+T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expression programs. We explored the role of gene silencing by the histone methyltransferase Suv39h1. In murine CD8+T cells activated afterListeria monocytogenesinfection, Suv39h1-dependent trimethylation of histone H3 lysine 9 controls the expression of a set of stem cell–related memory genes. Single-cell RNA sequencing revealed a defect in silencing of stem/memory genes selectively inSuv39h1-defective T cell effectors. As a result,Suv39h1-defective CD8+T cells show sustained survival and increased long-term memory reprogramming capacity. Thus, Suv39h1 plays a critical role in marking chromatin to silence stem/memory genes during CD8+T effector terminal differentiation.

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Dexamethasone Effect on Embryonic Chick Respiratory Epithelium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053905 ◽

1982 ◽

Vol 40 ◽

pp. 248-249

Author(s):

M.R. Richter ◽

R.V. Blystone

Keyword(s):

Lung Development ◽

Critical Role ◽

Respiratory Epithelium ◽

Chick Embryos ◽

Embryonic Chick ◽

White Leghorn ◽

Lung Maturation ◽

Synthetic Analogs ◽

Lung Physiology ◽

Avian Lung

Dexamethasone and other synthetic analogs of corticosteroids have been employed clinically as enhancers of lung development. The mechanism(s) by which this steroid induction of later lung maturation operates is not clear. This study reports the effect on lung epithelia of dexamethasone administered at different intervals during development. White Leghorn chick embryos were used so as to remove possible maternal and placental influences on the exogenously applied steroid. Avian lung architecture does vary from mammals; however, respiratory surfactant produced by the lung epithelia serves an equally critical role in avian lung physiology.

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An atomic resolution study of a carbide phase in platinum

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100120503 ◽

1992 ◽

Vol 50 (1) ◽

pp. 20-21

Author(s):

M.J. Witcomb ◽

M.A. O'Keefe ◽

CJ. Echer ◽

C. Nelson ◽

J.H. Turner ◽

...

Keyword(s):

Solid Solution ◽

Carbon Atom ◽

Carbide Phase ◽

Structural Changes ◽

Critical Role ◽

Alloy System ◽

Atomic Resolution ◽

Excess Carbon ◽

Interstitial Carbon ◽

Resolution Study

Under normal circumstances, Pt dissolves only a very small amount of interstitial carbon in solid solution. Even so, an appropriate quench/age treatment leads to the formation of stable Pt2C {100} plate precipitates. Excess (quenched-in) vacancies play a critical role in the process by accommodating the volume and structural changes that accompany the transformation. This alloy system exhibits other interesting properties. Due to a large vacancy/carbon atom binding energy, Pt can absorb excess carbon at high temperatures in a carburizing atmosphere. In regions rich in carbon and vacancies, another carbide phase, Pt7C which undergoes an order-disorder reaction was formed. The present study of Pt carburized at 1160°C and aged at 515°C shows that other carbides in the PtxC series can be produced.

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