The Chromatin Remodeling Protein CHD-1 and the EFL-1/DPL-1 Transcription Factor Cooperatively Down Regulate CDK-2 to Control SAS-6 Levels and Centriole Number

Centrioles are submicron-scale, barrel-shaped organelles typically found in pairs, and play important roles in ciliogenesis and bipolar spindle assembly. In general, successful execution of centriole-dependent processes is highly reliant on the ability of the cell to stringently control centriole number. This in turn is mainly achieved through the precise duplication of centrioles during each S phase. Aberrations in centriole duplication disrupt spindle assembly and cilia based signaling and have been linked to cancer, primary microcephaly and a variety of growth disorders. Studies aimed at understanding how centriole duplication is controlled have mainly focused on the post-translational regulation of two key components of this pathway: the master regulatory kinase ZYG-1/Plk4 and the scaffold component SAS-6. In contrast, how transcriptional control mechanisms might contribute to this process have not been well explored. Here we show that the chromatin remodeling protein CHD-1 contributes to the regulation of centriole duplication in the C. elegans embryo. Specifically, we find that loss of CHD-1 or inactivation of its ATPase activity can restore embryonic viability and centriole duplication to a strain expressing insufficient ZYG-1 activity. Interestingly, loss of CHD-1 is associated with increases in the levels of two ZYG-1-binding partners: SPD-2, the centriole receptor for ZYG-1 and SAS-6. Finally, we explore transcriptional regulatory networks governing centriole duplication and find that CHD-1 and a second transcription factor, EFL-1/DPL-1 cooperate to down regulate expression of CDK-2, which in turn promotes SAS-6 protein levels. Disruption of this regulatory network results in the overexpression of SAS-6 and the production of extra centrioles.

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Homeobox Genes and Melatonin Synthesis: Regulatory Roles of the Cone-Rod Homeobox Transcription Factor in the Rodent Pineal Gland

BioMed Research International ◽

10.1155/2014/946075 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Kristian Rohde ◽

Morten Møller ◽

Martin Fredensborg Rath

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Circadian Rhythm ◽

Pineal Gland ◽

Transcriptional Control ◽

Homeobox Genes ◽

Control Mechanisms ◽

Camp Response Element ◽

Homeobox Transcription Factor ◽

Melatonin Production

Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent,Aanatgene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction ofAanattranscription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specificAanatexpression. Based on recent advances in our understanding ofCrxin the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specificAanatexpression and by facilitating cAMP response element-based circadian melatonin production.

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Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712365115 ◽

2017 ◽

Vol 114 (52) ◽

pp. E11180-E11189 ◽

Cited By ~ 14

Author(s):

Kesavan Meganathan ◽

Emily M. A. Lewis ◽

Paul Gontarz ◽

Shaopeng Liu ◽

Edouard G. Stanley ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Transcription Factor ◽

Embryonic Stem Cells ◽

Chromatin Remodeling ◽

Human Embryonic Stem Cells ◽

Regulatory Networks ◽

Embryonic Stem ◽

Molecular Networks ◽

Cortical Interneurons

Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties. We defined transcriptome changes accompanying this process and integrated these data with direct transcriptional targets of NKX2-1, a transcription factor controlling MGE specification. This analysis defined NKX2-1–associated genes with enriched expression during MGE specification and cIN differentiation, including known and previously unreported transcription factor targets with likely roles in MGE specification, and other target classes regulating cIN migration and function. NKX2-1–associated peaks were enriched for consensus binding motifs for NKX2-1, LHX, and SOX transcription factors, suggesting roles in coregulating MGE gene expression. Among the NKX2-1 direct target genes with cIN-enriched expression was CHD2, which encodes a chromatin remodeling protein mutated to cause human epilepsies. Accordingly, CHD2 deficiency impaired cIN specification and altered later electrophysiological function, while CHD2 coassociated with NKX2-1 at cis-regulatory elements and was required for their transactivation by NKX2-1 in MGE-like progenitors. This analysis identified several aspects of gene-regulatory networks underlying human MGE specification and suggested mechanisms by which NKX2-1 acts with chromatin remodeling activities to regulate gene expression programs underlying cIN development.

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Multi-omic regulatory networks capture downstream effects of kinase inhibition in Mycobacterium tuberculosis

npj Systems Biology and Applications ◽

10.1038/s41540-020-00164-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Albert T. Young ◽

Xavier Carette ◽

Michaela Helmel ◽

Hanno Steen ◽

Robert N. Husson ◽

...

Keyword(s):

Transcription Factor ◽

Mycobacterium Tuberculosis ◽

Regulatory Network ◽

Regulatory Networks ◽

Protein Interaction Data ◽

Kinase Inhibition ◽

Protein Protein Interaction ◽

Downstream Effects ◽

Regulate Cell Growth ◽

Regulatory Effects

AbstractThe ability of Mycobacterium tuberculosis (Mtb) to adapt to diverse stresses in its host environment is crucial for pathogenesis. Two essential Mtb serine/threonine protein kinases, PknA and PknB, regulate cell growth in response to environmental stimuli, but little is known about their downstream effects. By combining RNA-Seq data, following treatment with either an inhibitor of both PknA and PknB or an inactive control, with publicly available ChIP-Seq and protein–protein interaction data for transcription factors, we show that the Mtb transcription factor (TF) regulatory network propagates the effects of kinase inhibition and leads to widespread changes in regulatory programs involved in cell wall integrity, stress response, and energy production, among others. We also observe that changes in TF regulatory activity correlate with kinase-specific phosphorylation of those TFs. In addition to characterizing the downstream regulatory effects of PknA/PknB inhibition, this demonstrates the need for regulatory network approaches that can incorporate signal-driven transcription factor modifications.

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High-throughput single-cell chromatin accessibility CRISPR screens enable unbiased identification of regulatory networks in cancer

Nature Communications ◽

10.1038/s41467-021-23213-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sarah E. Pierce ◽

Jeffrey M. Granja ◽

William J. Greenleaf

Keyword(s):

Transcription Factor ◽

Single Cell ◽

Cancer Cells ◽

High Throughput ◽

Regulatory Networks ◽

Temporal Dynamics ◽

Chromatin Accessibility ◽

Regulatory Regions ◽

Factor Binding ◽

Genome Wide

AbstractChromatin accessibility profiling can identify putative regulatory regions genome wide; however, pooled single-cell methods for assessing the effects of regulatory perturbations on accessibility are limited. Here, we report a modified droplet-based single-cell ATAC-seq protocol for perturbing and evaluating dynamic single-cell epigenetic states. This method (Spear-ATAC) enables simultaneous read-out of chromatin accessibility profiles and integrated sgRNA spacer sequences from thousands of individual cells at once. Spear-ATAC profiling of 104,592 cells representing 414 sgRNA knock-down populations reveals the temporal dynamics of epigenetic responses to regulatory perturbations in cancer cells and the associations between transcription factor binding profiles.

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Transcriptional Control of Parturition: Insights from Gene Regulation Studies in the Myometrium

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaab024 ◽

2021 ◽

Author(s):

Nawrah Khader ◽

Virlana M Shchuka ◽

Oksana Shynlova ◽

Jennifer A Mitchell

Keyword(s):

Transcription Factors ◽

Regulatory Networks ◽

Transcriptional Control ◽

Progesterone Receptors ◽

Activator Protein 1 ◽

Transcriptional Regulatory Networks ◽

Regulatory Pathways ◽

Transcriptional Regulatory ◽

Mechanistic Basis ◽

Labour Onset

Abstract The onset of labour is a culmination of a series of highly coordinated and preparatory physiological events that take place throughout the gestational period. In order to produce the associated contractions needed for fetal delivery, smooth muscle cells in the muscular layer of the uterus (i.e. myometrium) undergo a transition from quiescent to contractile phenotypes. Here, we present the current understanding of the roles transcription factors play in critical labour-associated gene expression changes as part of the molecular mechanistic basis for this transition. Consideration is given to both transcription factors that have been well-studied in a myometrial context, i.e. activator protein 1 (AP-1), progesterone receptors (PRs), estrogen receptors (ERs), and nuclear factor kappa B (NF-κB), as well as additional transcription factors whose gestational event-driving contributions have been demonstrated more recently. These transcription factors may form pregnancy- and labour- associated transcriptional regulatory networks in the myometrium to modulate the timing of labour onset. A more thorough understanding of the transcription factor-mediated, labour-promoting regulatory pathways holds promise for the development of new therapeutic treatments that can be used for the prevention of preterm labour in at-risk women.

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Glucocorticoid receptor wields chromatin interactions to tune transcription for cytoskeleton stabilization in podocytes

Communications Biology ◽

10.1038/s42003-021-02209-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Hong Wang ◽

Aiping Duan ◽

Jing Zhang ◽

Qi Wang ◽

Yuexian Xing ◽

...

Keyword(s):

Transcription Factor ◽

Glucocorticoid Receptor ◽

Protective Effect ◽

Histone Modification ◽

Regulatory Networks ◽

Target Gene ◽

Regulatory Elements ◽

Chromatin Interactions ◽

Super Enhancer

AbstractElucidating transcription mediated by the glucocorticoid receptor (GR) is crucial for understanding the role of glucocorticoids (GCs) in the treatment of diseases. Podocyte is a useful model for studying GR regulation because GCs are the primary medication for podocytopathy. In this study, we integrated data from transcriptome, transcription factor binding, histone modification, and genome topology. Our data reveals that the GR binds and activates selective regulatory elements in podocyte. The 3D interactome captured by HiChIP facilitates the identification of remote targets of GR. We found that GR in podocyte is enriched at transcriptional interaction hubs and super-enhancers. We further demonstrate that the target gene of the top GR-associated super-enhancer is indispensable to the effective functioning of GC in podocyte. Our findings provided insights into the mechanisms underlying the protective effect of GCs on podocyte, and demonstrate the importance of considering transcriptional interactions in order to fine-map regulatory networks of GR.

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A Global Vista of the Epigenomic State of the Mouse Submandibular Gland

Journal of Dental Research ◽

10.1177/00220345211012000 ◽

2021 ◽

pp. 002203452110120

Author(s):

C. Gluck ◽

S. Min ◽

A. Oyelakin ◽

M. Che ◽

E. Horeth ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Control ◽

Expression Patterns ◽

Global Gene Expression ◽

Regulatory Elements ◽

Specific Gene ◽

Submandibular Salivary Gland ◽

Data Sets ◽

Control Mechanisms ◽

Chromatin Immunoprecipitation Sequencing

The parotid, submandibular, and sublingual glands represent a trio of oral secretory glands whose primary function is to produce saliva, facilitate digestion of food, provide protection against microbes, and maintain oral health. While recent studies have begun to shed light on the global gene expression patterns and profiles of salivary glands, particularly those of mice, relatively little is known about the location and identity of transcriptional control elements. Here we have established the epigenomic landscape of the mouse submandibular salivary gland (SMG) by performing chromatin immunoprecipitation sequencing experiments for 4 key histone marks. Our analysis of the comprehensive SMG data sets and comparisons with those from other adult organs have identified critical enhancers and super-enhancers of the mouse SMG. By further integrating these findings with complementary RNA-sequencing based gene expression data, we have unearthed a number of molecular regulators such as members of the Fox family of transcription factors that are enriched and likely to be functionally relevant for SMG biology. Overall, our studies provide a powerful atlas of cis-regulatory elements that can be leveraged for better understanding the transcriptional control mechanisms of the mouse SMG, discovery of novel genetic switches, and modulating tissue-specific gene expression in a targeted fashion.

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A UV-Induced Mutation in Neurospora That Affects Translational Regulation in Response to Arginine

Genetics ◽

10.1093/genetics/142.1.117 ◽

1996 ◽

Vol 142 (1) ◽

pp. 117-127 ◽

Cited By ~ 3

Author(s):

Michael Freitag ◽

Nelima Dighde ◽

Matthew S Sachs

Keyword(s):

Translational Control ◽

Translational Regulation ◽

Fusion Gene ◽

Mrna Translation ◽

Small Subunit ◽

Upstream Open Reading Frame ◽

Control Mechanisms ◽

Carbamoyl Phosphate ◽

Altered Expression ◽

Reading Frame

The Neurospora crmsu arg-2 gene encodes the small subunit of arginine-specific carbamoyl phosphate synthetase. The levels of arg-2 mRNA and mRNA translation are negatively regulated by arginine. An upstream open reading frame (uORF) in the transcript’s 5′ region has been implicated in arginine-specific control. An arg-2-hph fusion gene encoding hygromycin phosphotransferase conferred arginine-regulated resistance to hygromycin when introduced into N. crassa. We used an arg-2-hph strain to select for UV-induced mutants that grew in the presence of hygromycin and arginine, and we isolated 46 mutants that had either of two phenotypes. One phenotype indicated altered expression of both arg-2-hph and urg-2 genes; the other, altered expression of urg-2-hph but not arg-2. One of the latter mutations, which was genetically closely linked to arg-2-hph, was recovered from the 5′ region of the arg-2-hph gene using PCR. Sequence analyses and transformation experiments revealed a mutation at uORF codon 12 (Asp to Asn) that abrogated negative regulation. Examination of the distribution of ribosomes on arg-2-hph transcripts showed that loss of regulation had a translational component, indicating the uORF sequence was important for Arg-specific translational control. Comparisons with other uORFS suggest common elements in translational control mechanisms.

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Construction and analysis of dynamic transcription factor regulatory networks in the progression of glioma

Scientific Reports ◽

10.1038/srep15953 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 8

Author(s):

Yongsheng Li ◽

Tingting Shao ◽

Chunjie Jiang ◽

Jing Bai ◽

Zishan Wang ◽

...

Keyword(s):

Transcription Factor ◽

Regulatory Networks

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Characterization of the BCR promoter in Philadelphia chromosome-positive and -negative cell lines.

Molecular and Cellular Biology ◽

10.1128/mcb.11.4.1854 ◽

1991 ◽

Vol 11 (4) ◽

pp. 1854-1860 ◽

Cited By ~ 18

Author(s):

N P Shah ◽

O N Witte ◽

C T Denny

Keyword(s):

Transcription Factor ◽

Cell Lines ◽

Transcription Initiation ◽

Transcriptional Control ◽

Philadelphia Chromosome ◽

Gc Content ◽

Cellular Transformation ◽

Nucleotide Sequence Analysis ◽

Coding Sequences ◽

Gene Assay

The t(9;22) Philadelphia chromosome translocation fuses 5' regulatory and coding sequences of the BCR gene to the c-ABL proto-oncogene. This results in the formation of hybrid BCR-ABL mRNAs and proteins. The shift in ABL transcriptional control to the BCR promoter may play a role in cellular transformation mediated by this rearrangement. We have functionally localized the BCR promoter to a region 1 kb 5' of BCR exon 1 coding sequences by using a chloramphenicol acetyltransferase reporter gene assay. Nucleotide sequence analysis of this region revealed many consensus binding sequences for transcription factor SP1 as well as two potential CCAAT box binding factor sites and one putative helix-loop-helix transcription factor binding site. No TATA-like or "initiator" element sequences were found. Because of low steady-state levels of BCR mRNA and the high GC content (78%) of the promoter region, definitive mapping of transcription start sites required artificial amplification of BCR promoter-directed transcripts. Overexpression from the BCR promoter in a COS cell system was effective in demonstrating multiple transcription initiation sites. In order to assess the effects of chromosomal translocation on the transcriptional control of the BCR gene, we determined S1 nuclease protection patterns of poly(A)+ RNA from tumor cell lines. No differences were observed in the locations and levels of BCR transcription initiation sites between those lines that harbored the t(9;22) translocation and those that did not. This demonstrates that BCR promoter function remains intact in spite of genomic rearrangement. The BCR promoter is structurally similar to the ABL promoters. Together, this suggests that the structural fusion of BCR-ABL and not its transcriptional deregulation is primarily responsible for the transforming effect of the t(9;22) translocation.

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