KMT2B and Neuronal Transdifferentiation: Bridging Basic Chromatin Mechanisms to Disease Actionability

The role of bona fide epigenetic regulators in the process of neuronal transdifferentiation was until recently largely uncharacterized, despite their key role in the physiological processes of neural fate acquisition and maintenance. In this commentary, we describe the main findings of our recent paper “KMT2B is selectively required for neuronal transdifferentiation, and its loss exposes dystonia candidate genes,” where we investigated the role of this histone H3K4 methyltransferase during mouse embryonic fibroblasts (MEFs) to induced neuronal cells (iNs) direct conversion. Indeed, Kmt2b–/– MEFs, transduced with three neuronal-specific transcription factors (TFs), Brn2, Ascl1, and Myt1l, show lower transdifferentiation efficiency, defective iN maturation, and augmented alternative cell fates acquisition, with respect to controls. Here, we went beyond the data, hypothesizing how KMT2B executes its fundamental role. In particular, we supposed that MYT1L, which has been proven to be fundamental for iN maturation and the switch-off of alternative cell fates, directly or indirectly needs KMT2B. Indeed, KMT2B could be important both to make MYT1L-target genes accessible, because MYT1L is not a pioneer TF and preferentially binds to open chromatin, and to activate MYT1L-downstream genes.

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Identification of a novel enhancer of CEBPE essential for granulocytic differentiation

Blood ◽

10.1182/blood.2018886077 ◽

2019 ◽

Vol 133 (23) ◽

pp. 2507-2517 ◽

Cited By ~ 5

Author(s):

Pavithra Shyamsunder ◽

Mahalakshmi Shanmugasundaram ◽

Anand Mayakonda ◽

Pushkar Dakle ◽

Weoi Woon Teoh ◽

...

Keyword(s):

Target Genes ◽

Core Promoter ◽

Transcriptional Start Site ◽

Open Chromatin ◽

Sequencing Data ◽

Granulocytic Differentiation ◽

Circular Chromosome ◽

Chromosome Conformation ◽

Guide Rna

Abstract CCAAT/enhancer binding protein ε (CEBPE) is an essential transcription factor for granulocytic differentiation. Mutations of CEBPE occur in individuals with neutrophil-specific granule deficiency (SGD), which is characterized by defects in neutrophil maturation. Cebpe-knockout mice also exhibit defects in terminal differentiation of granulocytes, a phenotype reminiscent of SGD. Analysis of DNase I hypersensitive sites sequencing data revealed an open chromatin region 6 kb downstream of the transcriptional start site of Cebpe in murine myeloid cells. We identified an interaction between this +6-kb region and the core promoter of Cebpe using circular chromosome conformation capture sequencing (4C-seq). To understand the role of this putative enhancer in transcriptional regulation of Cebpe, we targeted it using catalytically inactive Cas9 fused to Krüppel-associated box (KRAB) domain and observed a significant downregulation of transcript and protein levels of CEBPE in cells expressing guide RNA targeting the +6-kb region. To further investigate the role of this novel enhancer further in myelopoiesis, we generated mice with deletion of this region using CRISPR/Cas9 technology. Germline deletion of the +6-kb enhancer resulted in reduced levels of CEBPE and its target genes and caused a severe block in granulocytic differentiation. We also identified binding of CEBPA and CEBPE to the +6-kb enhancer, which suggests their role in regulating the expression of Cebpe. In summary, we have identified a novel enhancer crucial for regulating expression of Cebpe and required for normal granulocytic differentiation.

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Two different activities of Suppressor of Hairless during wing development in Drosophila

Development ◽

10.1242/dev.127.16.3553 ◽

2000 ◽

Vol 127 (16) ◽

pp. 3553-3566 ◽

Cited By ~ 3

Author(s):

T. Klein ◽

L. Seugnet ◽

M. Haenlin ◽

A. Martinez Arias

Keyword(s):

Target Genes ◽

Transmembrane Protein ◽

Current Model ◽

Notch Pathway ◽

Notch Signalling ◽

Wing Development ◽

Transcription Activator ◽

Cell Fates ◽

H Protein

The Notch pathway plays a crucial and universal role in the assignation of cell fates during development. In Drosophila, Notch is a transmembrane protein that acts as a receptor of two ligands Serrate and delta. The current model of Notch signal transduction proposes that Notch is activated upon binding its ligands and that this leads to the cleavage and release of its intracellular domain (also called Nintra). Nintra translocates to the nucleus where it forms a dimeric transcription activator with the Su(H) protein. In contrast with this activation model, experiments with the vertebrate homologue of Su(H), CBF1, suggest that, in vertebrates, Nintra converts CBF1 from a repressor into an activator. Here we have assessed the role of Su(H) in Notch signalling during the development of the wing of Drosophila. Our results show that, during this process, Su(H) can activate the expression of some Notch target genes and that it can do so without the activation of the Notch pathway or the presence of Nintra. In contrast, the activation of other Notch target genes requires both Su(H) and Nintra, and, in the absence of Nintra, Su(H) acts as a repressor. We also find that the Hairless protein interacts with Notch signalling during wing development and inhibits the activity of Su(H). Our results suggest that, in Drosophila, the activation of Su(H) by Notch involve the release of Su(H) from an inhibitory complex, which contains the Hairless protein. After its release Su(H) can activate gene expression in absence of Nintra.

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A novel role of MNT as a negative regulator of REL and the NF-κB pathway

Oncogenesis ◽

10.1038/s41389-020-00298-4 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Judit Liaño-Pons ◽

M. Carmen Lafita-Navarro ◽

Lorena García-Gaipo ◽

Carlota Colomer ◽

Javier Rodríguez ◽

...

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Transcriptional Regulator ◽

Negative Regulator ◽

Biological Processes ◽

Helix Loop Helix ◽

Bona Fide ◽

E Boxes ◽

Independent Protein

AbstractMNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix–loop–helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT–REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT–REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.

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Role of the Forkhead Transcription Factors Fd4 and Fd5 During Drosophila Leg Development

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.723927 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mireya Ruiz-Losada ◽

Cristian Pérez-Reyes ◽

Carlos Estella

Keyword(s):

Transcription Factors ◽

Target Genes ◽

Cell Fates ◽

Forkhead Transcription Factors ◽

Leg Development ◽

Sex Comb ◽

And Function ◽

Male Specific ◽

Redundant Role

Appendage development requires the coordinated function of signaling pathways and transcription factors to pattern the leg along the three main axes: the antero-posterior (AP), proximo-distal (PD), and dorso-ventral (DV). The Drosophila leg DV axis is organized by two morphogens, Decapentaplegic (Dpp), and Wingless (Wg), which direct dorsal and ventral cell fates, respectively. However, how these signals regulate the differential expression of its target genes is mostly unknown. In this work, we found that two members of the Drosophila forkhead family of transcription factors, Fd4 and Fd5 (also known as fd96Ca and fd96Cb), are identically expressed in the ventro-lateral domain of the leg imaginal disc in response to Dpp signaling. Here, we analyze the expression regulation and function of these genes during leg development. We have generated specific mutant alleles for each gene and a double fd4/fd5 mutant chromosome to study their function during development. We highlight the redundant role of the fd4/fd5 genes during the formation of the sex comb, a male specific structure that appears in the ventro-lateral domain of the prothoracic leg.

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The role of STAT3 in the colorectal cancer therapy

Journal of Medical Science ◽

10.20883/medical.e427 ◽

2020 ◽

pp. e427

Author(s):

Katarzyna Papierska ◽

Violetta Krajka-Kuźniak

Keyword(s):

Colorectal Cancer ◽

Transcriptional Activation ◽

Target Genes ◽

Cancer Chemoprevention ◽

Malignant Tumour ◽

The Elderly ◽

The United States ◽

The European Union ◽

Physiological Processes

Colorectal cancer is a malignant tumour of the digestive system, more common in the elderly than in younger individuals. The incidence rate in the United States and the European Union is increasing by an average of 4.2% to 4.6% annually. There is emerging evidence that deregulation of the signalling pathway and abnormal expression and activation of genes is the main reason for the development of colorectal cancer. Signal transducer and activator of transcription (STAT3) is a transcription factor of signal transduction and transcriptional activation of target genes which plays important roles in proliferation, differentiation, apoptosis and other physiological processes. It has been confirmed that abnormal activation of STAT3 is involved in the development of tumours, so the identification of STAT3 inhibitors is a promising strategy for cancer chemoprevention and treatment of colorectal cancer. In this review, the roles of STAT3 in the pathogenesis and treatment of colorectal cancer are discussed.

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Noncanonical Constitutive Androstane Receptor Signaling in Gene Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms21186735 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6735

Author(s):

Yuliya A. Pustylnyak ◽

Lyudmila F. Gulyaeva ◽

Vladimir O. Pustylnyak

Keyword(s):

Cell Biology ◽

Energy Homeostasis ◽

Hormone Receptors ◽

Target Genes ◽

Constitutive Androstane Receptor ◽

Steroid Hormone Receptors ◽

Metabolizing Enzymes ◽

Physiological Processes ◽

Genes Encoding

The constitutive androstane receptor (CAR, NR1I3) is extremely important for the regulation of many physiological processes, especially xenobiotic (drug) metabolism and transporters. CAR differs from steroid hormone receptors in that it can be activated using structurally unrelated chemicals, both through direct ligand-binding and ligand-independent (indirect) mechanisms. By binding to specific responsive elements on DNA, CAR increases the expression of its target genes encoding drug-metabolizing enzymes and transporters. Therefore, CAR is mainly characterized as a ligand-dependent or ligand-independent transcription factor, and the induction of gene expression is considered the canonical mode of CAR action. Consistent with its central role in xenobiotic metabolism, CAR signaling includes a collection of mechanisms that are employed alongside the core transcriptional machinery of the receptor. These so-called noncanonical CAR pathways allow the receptor to coordinate the regulation of many aspects of cell biology. In this mini-review, we review noncanonical CAR signaling, paying special attention to the role of CAR in energy homeostasis and cell proliferation.

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Roles of lysine-specific demethylase 1 (LSD1) in homeostasis and diseases

Journal of Biomedical Science ◽

10.1186/s12929-021-00737-3 ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Dongha Kim ◽

Keun Il Kim ◽

Sung Hee Baek

Keyword(s):

Stem Cells ◽

Epithelial To Mesenchymal Transition ◽

Regulation Of Gene Expression ◽

Cancer Microenvironment ◽

Mesenchymal Transition ◽

Physiological Processes ◽

Lysine Specific Demethylase ◽

Histone H3k4 ◽

Cerebral Physiology

AbstractLysine-specific demethylase 1 (LSD1) targets mono- or di-methylated histone H3K4 and H3K9 as well as non-histone substrates and functions in the regulation of gene expression as a transcriptional repressor or activator. This enzyme plays a pivotal role in various physiological processes, including development, differentiation, inflammation, thermogenesis, neuronal and cerebral physiology, and the maintenance of stemness in stem cells. LSD1 also participates in pathological processes, including cancer as the most representative disease. It promotes oncogenesis by facilitating the survival of cancer cells and by generating a pro-cancer microenvironment. In this review, we discuss the role of LSD1 in several aspects of cancer, such as hypoxia, epithelial-to-mesenchymal transition, stemness versus differentiation of cancer stem cells, as well as anti-tumor immunity. Additionally, the current understanding of the involvement of LSD1 in various other pathological processes is discussed.

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Histone H3K4 Methyltransferases as Targets for Drug-Resistant Cancers

Biology ◽

10.3390/biology10070581 ◽

2021 ◽

Vol 10 (7) ◽

pp. 581

Author(s):

Liu Yang ◽

Mingli Jin ◽

Kwang Won Jeong

Keyword(s):

Drug Resistance ◽

Protein Interactions ◽

Target Genes ◽

Triple Negative ◽

Castration Resistant Prostate Cancer ◽

Protein Protein Interactions ◽

Castration Resistant ◽

Histone H3k4 ◽

H3k4 Methyltransferases

The KMT2 (MLL) family of proteins, including the major histone H3K4 methyltransferase found in mammals, exists as large complexes with common subunit proteins and exhibits enzymatic activity. SMYD, another H3K4 methyltransferase, and SET7/9 proteins catalyze the methylation of several non-histone targets, in addition to histone H3K4 residues. Despite these structural and functional commonalities, H3K4 methyltransferase proteins have specificity for their target genes and play a role in the development of various cancers as well as in drug resistance. In this review, we examine the overall role of histone H3K4 methyltransferase in the development of various cancers and in the progression of drug resistance. Compounds that inhibit protein–protein interactions between KMT2 family proteins and their common subunits or the activity of SMYD and SET7/9 are continuously being developed for the treatment of acute leukemia, triple-negative breast cancer, and castration-resistant prostate cancer. These H3K4 methyltransferase inhibitors, either alone or in combination with other drugs, are expected to play a role in overcoming drug resistance in leukemia and various solid cancers.

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90 YEARS OF PROGESTERONE: Progesterone and progesterone receptors in breast cancer: past, present, future

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0104 ◽

2020 ◽

Vol 65 (1) ◽

pp. T49-T63 ◽

Cited By ~ 1

Author(s):

Kathryn B Horwitz ◽

Carol A Sartorius

Keyword(s):

Breast Cancer ◽

Breast Cancer Incidence ◽

Progesterone Receptors ◽

Predictive Marker ◽

Breast Cancers ◽

Physiological Processes ◽

History Of ◽

Bona Fide ◽

Treatment Responses

Progesterone and progesterone receptors (PR) have a storied albeit controversial history in breast cancers. As endocrine therapies for breast cancer progressed through the twentieth century from oophorectomy to antiestrogens, it was recognized in the 1970s that the presence of estrogen receptors (ER) alone could not efficiently predict treatment responses. PR, an estrogen regulated protein, became the first prognostic and predictive marker of response to endocrine therapies. It remains today as the gold standard for predicting the existence of functional, targetable ER in breast malignancies. PRs were subsequently identified as highly structured transcription factors that regulate diverse physiological processes in breast cancer cells. In the early 2000s, the somewhat surprising finding that prolonged use of synthetic progestin-containing menopausal hormone therapies was associated with increased breast cancer incidence raised new questions about the role of PR in ‘tumorigenesis’. Most recently, PR have been linked to expansion of cancer stem cells that are postulated to be the principal cells reactivated in occult or dormant disease. Other studies establish PR as dominant modulators of ER activity. Together, these findings mark PR as bona fide targets for progestin or antiprogestin therapies, yet their diverse actions have confounded that use. Here we summarize the early history of PR in breast cancer; debunk the theory that progesterone causes cancer; discuss recent discoveries that PR regulate cell heterogeneity; attempt to unify theories describing PR as either good or bad actors in tumors; and discuss emerging areas of research that may help explain this enigmatic hormone and receptor.

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CHARACTERISTICS OF miRNA INTERACTION WITH mRNA GENES OF T. AESTIVUM C2H2, ERF, GRAS TRANSCRIPTION FACTORS FAMILIES

SERIES OF BIOLOGICAL AND MEDICAL ◽

10.32014/10.32014/2020.2519-1629.7 ◽

2020 ◽

Vol 2 (338) ◽

pp. 5-11

Author(s):

A. K. Rakhmetullina ◽

S. K. Turasheva ◽

A. A. Bolshoy ◽

A. T. Ivashchenko

Keyword(s):

Transcription Factors ◽

Binding Sites ◽

Molecular Mechanisms ◽

Target Genes ◽

Abiotic And Biotic Stresses ◽

Biotic Stresses ◽

Gras Family ◽

Physiological Processes ◽

Nucleotide Interactions

The molecular mechanisms for increasing plant productivity remain poorly understood. Genes of C2H2, GRAS, ERF transcription factors (TFs) families play a key role in the physiological processes of plants, including wheat. In recent years, the important role of miRNAs in the regulation of the expression of many genes involved in the formation of productivity has been established. Wheat miRNA (mRNA-inhibiting RNA) target genes are involved in the regulation of the development of flowers, seeds, root, shoots, and responses to abiotic and biotic stresses. The miRNAs binding sites in mRNAs of C2H2, ERF, GRAS TFs families were performed using the MirTarget program, which calculates the free energy of miRNA binding with mRNA, the schemes and positions of nucleotide interactions with binding sites. Wheat genes were used as the object of the study, since wheat is one of the main grain crops in Kazakhstan and in many other countries. The presence of miRNA binding sites with high nucleotide complementarity in mRNA of C2H2, ERF, GRAS TF genes of wheat was shown. All binding sites of these miRNAs were located in the CDS of mRNA target genes. Of the 125 miRNAs of T. aestivum, miR319-3p efficiently bound with mRNA of C2H2 family genes with the value of ΔG/ΔGm equal 91 %. miR7757-5p interacted with mRNA of ERF and GRAS family genes with the value of ΔG/ΔGm equal to 92 % and 90 % respectively. miR9778-5p bound with mRNA of C2H2, ERF, GRAS family genes to varying degrees. Each of the miR408-3p, miR9780-3p, and miR9778-5p had four target genes with the value of ΔG/ΔGm equal to 87 % and 89 %. These data indicate the dependency of C2H2, GRAS, ERF TFs families expression on miRNA. The obtained results expand the fundamental ideas about the regulatory mechanisms of miRNA in the process of plant growth and development.

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