Integrative analysis of the zinc finger transcription factor Lame duck in the Drosophila myogenic gene regulatory network

AbstractRenal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular populations with discrete physiological tasks. Knowledge about the terminal differentiation programs of each nephron segment has central importance for understanding kidney disease and to advance regenerative medicine, as mammalian nephrons grown in organoid cultures from pluripotent cells fail to terminally differentiate. Here, from a novel forward genetic screen using zebrafish we report the discovery that transcription factor AP-2 alpha (tfap2a) coordinates a gene regulatory network that controls the progression of nephron distal segment progenitors into the differentiated state. Overexpression of tfap2a rescued differentiation in mutants and caused ectopic expression of distal segment markers in wild-type nephrons, indicating tfap2a is sufficient to instigate the distal segment differentiation program. tfap2a/2b deficiency exacerbated distal nephron segment differentiation defects, revealing functional redundancy where tfap2a has a dominant role upstream of its family member. With further genetic studies, we assembled a blueprint of the tfap2a gene regulatory network during nephrogenesis. We demonstrate that tfap2a acts downstream of Iroquois homeobox 3b, a conserved distal lineage transcription factor. tfap2a controls a circuit consisting of irx1a, tfap2b, and genes encoding solute transporters that dictate the specialized metabolic functions of the distal nephron segments, and we show for the first time that this regulatory node is distinct from the pathway circuits controlling aspects such as apical-basal polarity and ciliogenesis during the differentiation process. Thus, our studies reveal new insights into the genetic control of differentiation, where tfap2a regulates the suite of segment transporter traits. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesis in vivo to make functional units that can facilitate organoid applications such as drug discovery and regenerative therapies.Summary StatementHere, we report for the first time that transcription factor AP-2 alpha (tfap2a) controls the progression from nephron progenitor into the fully differentiated state. This fundamentally deepens our knowledge about the genetic control of kidney development.

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The transcription factor Zic4 acts as a transdifferentiation switch

10.1101/2021.12.22.473838 ◽

2021 ◽

Author(s):

Matthias Christian Vogg ◽

Jaroslav Ferenc ◽

Wanda Christa Buzgariu ◽

Chrystelle Perruchoud ◽

Panagiotis Papasaikas ◽

...

Keyword(s):

Cell Cycle ◽

Transcription Factor ◽

Gene Regulatory Network ◽

Cell Fate ◽

Regulatory Network ◽

Molecular Mechanisms ◽

Model System ◽

Cell Identity ◽

Transcriptional Switch ◽

Gene Regulatory

The molecular mechanisms that maintain cell identities and prevent transdifferentiation remain mysterious. Interestingly, both dedifferentiation and transdifferentiation are transiently reshuffled during regeneration. Therefore, organisms that regenerate readily offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4 silencing is sufficient to induce transdifferentiation of tentacle into foot cells. We identified a Wnt-controlled Gene Regulatory Network that controls a transcriptional switch of cell identity. Furthermore, we show that this switch also controls the re-entry into the cell cycle. Our data indicate that maintenance of cell fate by a Wnt-controlled GRN is a key mechanism during both homeostasis and regeneration.

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Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network

eLife ◽

10.7554/elife.03346 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 47

Author(s):

Carine Gubelmann ◽

Petra C Schwalie ◽

Sunil K Raghav ◽

Eva Röder ◽

Tenagne Delessa ◽

...

Keyword(s):

Transcription Factor ◽

Cell Differentiation ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Whole Body ◽

Central Component ◽

Fat Cell ◽

Differentiation Potential ◽

Adipogenic Gene ◽

Gene Regulatory

Adipose tissue is a key determinant of whole body metabolism and energy homeostasis. Unraveling the regulatory mechanisms underlying adipogenesis is therefore highly relevant from a biomedical perspective. Our current understanding of fat cell differentiation is centered on the transcriptional cascades driven by the C/EBP protein family and the master regulator PPARγ. To elucidate further components of the adipogenic gene regulatory network, we performed a large-scale transcription factor (TF) screen overexpressing 734 TFs in mouse pre-adipocytes and probed their effect on differentiation. We identified 22 novel pro-adipogenic TFs and characterized the top ranking TF, ZEB1, as being essential for adipogenesis both in vitro and in vivo. Moreover, its expression levels correlate with fat cell differentiation potential in humans. Genomic profiling further revealed that this TF directly targets and controls the expression of most early and late adipogenic regulators, identifying ZEB1 as a central transcriptional component of fat cell differentiation.

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Improving plant gene regulatory network inference by integrative analysis of multi-omics and high resolution data sets

Current Opinion in Systems Biology ◽

10.1016/j.coisb.2020.07.010 ◽

2020 ◽

Vol 22 ◽

pp. 8-15

Author(s):

Yichun Qian ◽

Shao-shan Carol Huang

Keyword(s):

High Resolution ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Network Inference ◽

Integrative Analysis ◽

Data Sets ◽

Gene Regulatory Network Inference ◽

High Resolution Data ◽

Gene Regulatory ◽

Resolution Data

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A gene regulatory network controlled by the NAC transcription factor ANAC092/AtNAC2/ORE1 during salt-promoted senescence

The Plant Journal ◽

10.1111/j.1365-313x.2010.04151.x ◽

2010 ◽

Vol 62 (2) ◽

pp. 250-264 ◽

Cited By ~ 268

Author(s):

Salma Balazadeh ◽

Hamad Siddiqui ◽

Annapurna D. Allu ◽

Lilian P. Matallana-Ramirez ◽

Camila Caldana ◽

...

Keyword(s):

Transcription Factor ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Nac Transcription Factor ◽

Gene Regulatory

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Functional role of hub molecules in miRNA and transcription factor mediated gene regulatory network of colorectal and lung cancer

Gene Reports ◽

10.1016/j.genrep.2021.101129 ◽

2021 ◽

Vol 23 ◽

pp. 101129

Author(s):

Zishan Ahmed ◽

Chittabrata Mal

Keyword(s):

Lung Cancer ◽

Transcription Factor ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Functional Role ◽

Gene Regulatory

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BMP2-dependent gene regulatory network analysis reveals Klf4 as a novel transcription factor of osteoblast differentiation

Cell Death and Disease ◽

10.1038/s41419-021-03480-7 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Shuaitong Yu ◽

Jinqiang Guo ◽

Zheyi Sun ◽

Chujiao Lin ◽

Huangheng Tao ◽

...

Keyword(s):

Bone Marrow ◽

Transcription Factor ◽

Gene Regulatory Network ◽

Stromal Cells ◽

Regulatory Network ◽

Bone Marrow Stromal Cells ◽

Osteoblast Differentiation ◽

Marrow Stromal Cells ◽

Rna Seq ◽

Gene Regulatory

AbstractTranscription factors (TFs) regulate the expression of target genes, inducing changes in cell morphology or activities needed for cell fate determination and differentiation. The BMP signaling pathway is widely regarded as one of the most important pathways in vertebrate skeletal biology, of which BMP2 is a potent inducer, governing the osteoblast differentiation of bone marrow stromal cells (BMSCs). However, the mechanism by which BMP2 initiates its downstream transcription factor cascade and determines the direction of differentiation remains largely unknown. In this study, we used RNA-seq, ATAC-seq, and animal models to characterize the BMP2-dependent gene regulatory network governing osteoblast lineage commitment. Sp7-Cre; Bmp2fx/fx mice (BMP2-cKO) were generated and exhibited decreased bone density and lower osteoblast number (n > 6). In vitro experiments showed that BMP2-cKO mouse bone marrow stromal cells (mBMSCs) had an impact on osteoblast differentiation and deficient cell proliferation. Osteogenic medium induced mBMSCs from BMP2-cKO mice and control were subjected to RNA-seq and ATAC-seq analysis to reveal differentially expressed TFs, along with their target open chromatin regions. Combined with H3K27Ac CUT&Tag during osteoblast differentiation, we identified 2338 BMP2-dependent osteoblast-specific active enhancers. Motif enrichment assay revealed that over 80% of these elements were directly targeted by RUNX2, DLX5, MEF2C, OASIS, and KLF4. We deactivated Klf4 in the Sp7 + lineage to validate the role of KLF4 in osteoblast differentiation of mBMSCs. Compared to the wild-type, Sp7-Cre; Klf4fx/+ mice (KLF4-Het) were smaller in size and had abnormal incisors resembling BMP2-cKO mice. Additionally, KLF4-Het mice had fewer osteoblasts and decreased osteogenic ability. RNA-seq and ATAC-seq revealed that KLF4 mainly “co-bound” with RUNX2 to regulate downstream genes. Given the significant overlap between KLF4- and BMP2-dependent NFRs and enriched motifs, our findings outline a comprehensive BMP2-dependent gene regulatory network specifically governing osteoblast differentiation of the Sp7 + lineage, in which Klf4 is a novel transcription factor.

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