Transcriptional Control of Cell Lineage Development in Epicardium-Derived Cells

Abstract Sex determination of the gonads begins with fate specification of gonadal supporting cells into either ovarian pre-granulosa cells or testicular Sertoli cells. This fate specification hinges on a balance of transcriptional control. Here we report that expression of the transcription factor RUNX1 is enriched in the fetal ovary in rainbow trout, turtle, mouse, goat, and human. In the mouse, RUNX1 marks the supporting cell lineage and becomes pre-granulosa cell-specific as the gonads differentiate. RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity and combined loss of RUNX1 and FOXL2 results in masculinization of fetal ovaries. At the chromatin level, RUNX1 occupancy overlaps partially with FOXL2 occupancy in the fetal ovary, suggesting that RUNX1 and FOXL2 target common sets of genes. These findings identify RUNX1, with an ovary-biased expression pattern conserved across species, as a regulator in securing the identity of ovarian-supporting cells and the ovary.

Download Full-text

Comprehensive mapping of the human cytokine gene regulatory network

10.1101/2020.05.05.079657 ◽

2020 ◽

Author(s):

CS Santoso ◽

Z Li ◽

S Lal ◽

S Yuan ◽

KA Gan ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Control ◽

Immune Cell ◽

Cell Lineage ◽

Cytokine Gene Expression ◽

Gene Promoters ◽

Cytokine Gene ◽

Cytokine Regulation ◽

Gene Regulatory ◽

Human Cytokine

SummaryProper cytokine gene expression is essential in development, homeostasis, and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we use enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1,380 interactions between 265 TFs and 108 cytokine gene promoters, greatly expanding the known repertoire of TF-cytokine gene interactions. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that synergistically modulate cytokine gene expression, and to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.

Download Full-text

Comprehensive mapping of the human cytokine gene regulatory network

Nucleic Acids Research ◽

10.1093/nar/gkaa1055 ◽

2020 ◽

Vol 48 (21) ◽

pp. 12055-12073

Author(s):

Clarissa S Santoso ◽

Zhaorong Li ◽

Sneha Lal ◽

Samson Yuan ◽

Kok Ann Gan ◽

...

Keyword(s):

Transcriptional Control ◽

Immune Cell ◽

Cell Lineage ◽

Cytokine Gene Expression ◽

Gene Promoters ◽

Rna Seq ◽

Cytokine Gene ◽

Cytokine Regulation ◽

Cytokine Genes ◽

Gene Regulatory

Abstract Proper cytokine gene expression is essential in development, homeostasis and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we used enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1380 interactions between 265 TFs and 108 cytokine gene promoters. Our eY1H-derived network greatly expands the known repertoire of TF–cytokine gene interactions and the set of TFs known to regulate cytokine genes. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that can be targeted with commercially-available drugs to synergistically modulate cytokine production. Finally, we integrated the eY1H data with single cell RNA-seq and phenotypic datasets to identify novel TF–cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.

Download Full-text

Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation

Nature Metabolism ◽

10.1038/s42255-020-00314-2 ◽

2020 ◽

Vol 2 (12) ◽

pp. 1443-1458

Author(s):

Chen Weng ◽

Jiajia Xi ◽

Haiyan Li ◽

Jian Cui ◽

Anniya Gu ◽

...

Keyword(s):

Cell Differentiation ◽

Beta Cell ◽

Single Cell ◽

Transcriptional Control ◽

Cell Lineage ◽

Lineage Analysis

Download Full-text

Faster, higher, stronger: timely and robust cell fate/identity commitment in stem cell lineages

Open Biology ◽

10.1098/rsob.180243 ◽

2019 ◽

Vol 9 (2) ◽

pp. 180243 ◽

Cited By ~ 2

Author(s):

Kun Liu ◽

Ke Xu ◽

Yan Song

Keyword(s):

Stem Cell ◽

Cell Fate ◽

Transcriptional Control ◽

Cell Lineage ◽

Cell Fate Specification ◽

Developmental Abnormalities ◽

Cell Lineages ◽

Identity Commitment ◽

Regulatory Strategies ◽

Stem Cell Lineage

Precise specification of cell fate or identity within stem cell lineages is critical for ensuring correct stem cell lineage progression and tissue homeostasis. Failure to specify cell fate or identity in a timely and robust manner can result in developmental abnormalities and diseases such as cancer. However, the molecular basis of timely cell fate/identity specification is only beginning to be understood. In this review, we discuss key regulatory strategies employed in cell fate specification and highlight recent results revealing how timely and robust cell fate/identity commitment is achieved through transcriptional control.

Download Full-text

RUNX1 safeguards the identity of the fetal ovary through an interplay with FOXL2

10.1101/598607 ◽

2019 ◽

Author(s):

Barbara Nicol ◽

Sara A. Grimm ◽

Frederic Chalmel ◽

Estelle Lecluze ◽

Maëlle Pannetier ◽

...

Keyword(s):

Granulosa Cell ◽

Sertoli Cells ◽

Transcriptional Control ◽

Cell Lineage ◽

Supporting Cell ◽

Supporting Cells ◽

Fate Specification ◽

Ovarian Granulosa Cells ◽

Fetal Ovary

AbstractSex determination of the gonads begins with fate specification of gonadal supporting cells into either ovarian granulosa cells or testicular Sertoli cells. This process of fate specification hinges on a balance of transcriptional control. We discovered that expression of the transcription factor RUNX1 is enriched in the fetal ovary in rainbow trout, turtle, mouse, goat and human. In the mouse, RUNX1 marks the supporting cell lineage and becomes granulosa cell-specific as the gonads differentiate. RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity, and combined loss of RUNX1 and FOXL2 results in masculinization of the fetal ovaries. At the chromatin level, RUNX1 occupancy overlaps partially with FOXL2 occupancy in the fetal ovary, suggesting that RUNX1 and FOXL2 target a common set of genes. These findings identify RUNX1, with an ovary-biased pattern conserved across species, as a novel regulator in securing the identity of ovarian supporting cells and the ovary.

Download Full-text

Genetic and epigenetic variation in the lineage specification of regulatory T cells

eLife ◽

10.7554/elife.07571 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 33

Author(s):

Aaron Arvey ◽

Joris van der Veeken ◽

George Plitas ◽

Stephen S Rich ◽

Patrick Concannon ◽

...

Keyword(s):

Treg Cell ◽

Transcriptional Control ◽

Cell Function ◽

Cell Lineage ◽

Control Program ◽

Regulatory Elements ◽

Treg Cells ◽

Epigenetic Variation ◽

Nucleotide Polymorphisms ◽

Lineage Specification

Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease.

Download Full-text

Nutrient-regulated gene expression in eukaryotes

Biochemical Society Symposium ◽

10.1042/bss0730085 ◽

2006 ◽

Vol 73 ◽

pp. 85-96 ◽

Cited By ~ 8

Author(s):

Richard J. Reece ◽

Laila Beynon ◽

Stacey Holden ◽

Amanda D. Hughes ◽

Karine Rébora ◽

...

Keyword(s):

Gene Expression ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Transcriptional Control ◽

Direct Interaction ◽

Signalling Pathways ◽

A Cell ◽

One Step ◽

Higher Eukaryotes ◽

Regulated Gene Expression

The recognition of changes in environmental conditions, and the ability to adapt to these changes, is essential for the viability of cells. There are numerous well characterized systems by which the presence or absence of an individual metabolite may be recognized by a cell. However, the recognition of a metabolite is just one step in a process that often results in changes in the expression of whole sets of genes required to respond to that metabolite. In higher eukaryotes, the signalling pathway between metabolite recognition and transcriptional control can be complex. Recent evidence from the relatively simple eukaryote yeast suggests that complex signalling pathways may be circumvented through the direct interaction between individual metabolites and regulators of RNA polymerase II-mediated transcription. Biochemical and structural analyses are beginning to unravel these elegant genetic control elements.

Download Full-text