Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia

Studying the roles of Hox genes in normal and pathological development of skin and hair requires identification of downstream target genes in genetically defined animal models. We show that transgenic mice overexpressing Hoxc13 in differentiating keratinocytes of hair follicles develop alopecia, accompanied by a progressive pathological skin condition that resembles ichthyosis. Large-scale analysis of differential gene expression in postnatal skin of these mice identified 16 previously unknown and 13 known genes as presumptive Hoxc13 targets. The majority of these targets are downregulated and belong to a subgroup of genes that encode hair-specific keratin-associated proteins (KAPs). Genomic mapping using a mouse hamster radiation hybrid panel showed these genes to reside in a novel KAP gene cluster on mouse chromosome 16 in a region of conserved linkage with human chromosome 21q22.11. Furthermore, data obtained by Hoxc13/lacZ reporter gene analysis in mice that overexpress Hoxc13 suggest negative autoregulatory feedback control of Hoxc13 expression levels, thus providing an entry point for elucidating currently unknown mechanisms that are required for regulating quantitative levels of Hox gene expression. Combined, these results provide a framework for understanding molecular mechanisms of Hoxc13 function in hair growth and development.

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The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury

Journal of the American Society of Nephrology ◽

10.1681/asn.2019050534 ◽

2020 ◽

Vol 31 (4) ◽

pp. 716-730 ◽

Cited By ~ 1

Author(s):

Marc Johnsen ◽

Torsten Kubacki ◽

Assa Yeroslaviz ◽

Martin Richard Späth ◽

Jannis Mörsdorf ◽

...

Keyword(s):

Gene Expression ◽

Reperfusion Injury ◽

Caloric Restriction ◽

Molecular Mechanisms ◽

Target Genes ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hypoxic Preconditioning ◽

Preventive Strategies ◽

Gene Expression Signatures

BackgroundAlthough AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance.MethodsTo identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury.ResultsThe gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI.ConclusionsThis comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

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The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00450-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xiulin Jiang ◽

Baiyang Liu ◽

Zhi Nie ◽

Lincan Duan ◽

Qiuxia Xiong ◽

...

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Target Genes ◽

Rna Modification ◽

Biological Functions ◽

Rna Methylation ◽

Downstream Target ◽

Different Types ◽

M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

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Differences in Gene Expression between Wild Type and Hoxa1 Knockout Embryonic Stem Cells after Retinoic Acid Treatment or Leukemia Inhibitory Factor (LIF) Removal

Journal of Biological Chemistry ◽

10.1074/jbc.m414397200 ◽

2005 ◽

Vol 280 (16) ◽

pp. 16484-16498 ◽

Cited By ~ 59

Author(s):

Eduardo Martinez-Ceballos ◽

Pierre Chambon ◽

Lorraine J. Gudas

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Retinoic Acid ◽

Leukemia Inhibitory Factor ◽

Target Genes ◽

Hox Genes ◽

Es Cells ◽

Embryonic Stem ◽

Inhibitory Factor ◽

Hoxa Cluster

Homeobox (Hox) genes encode a family of transcription factors that regulate embryonic patterning and organogenesis. In embryos, alterations of the normal pattern of Hox gene expression result in homeotic transformations and malformations. Disruption of theHoxa1gene, the most 3′ member of the Hoxa cluster and a retinoic acid (RA) direct target gene, results in abnormal ossification of the skull, hindbrain, and inner ear deficiencies, and neonatal death. We have generated Hoxa1-/-embryonic stem (ES) cells (named Hoxa1-15) from Hoxa1-/-mutant blastocysts to study the Hoxa1 signaling pathway. We have characterized in detail these Hoxa1-/-ES cells by performing microarray analyses, and by this technique we have identified a number of putative Hoxa-1 target genes, including genes involved in bone development (e.g. Col1a1,Postn/Osf2, and the bone sialoprotein gene orBSP), genes that are expressed in the developing brain (e.g. Nnat,Wnt3a,BDNF,RhoB, andGbx2), and genes involved in various cellular processes (e.g. M-RAS,Sox17,Cdkn2b,LamA1,Col4a1,Foxa2,Foxq1,Klf5, andIgf2). Cell proliferation assays and Northern blot analyses of a number of ES cell markers (e.g. Rex1,Oct3/4,Fgf4, andBmp4) suggest that the Hoxa1 protein plays a role in the inhibition of cell proliferation by RA in ES cells. Additionally, Hoxa1-/-ES cells express high levels of various endodermal markers, includingGata4andDab2, and express much lessFgf5after leukemia inhibitory factor (LIF) withdrawal. Finally, we propose a model in which the Hoxa1 protein mediates repression of endodermal differentiation while promoting expression of ectodermal and mesodermal characteristics.

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Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

10.1101/2020.02.10.941872 ◽

2020 ◽

Author(s):

Connor Rogerson ◽

Samuel Ogden ◽

Edward Britton ◽

Yeng Ang ◽

Andrew D. Sharrocks ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Molecular Mechanisms ◽

Target Genes ◽

Prognostic Significance ◽

Gene Expression Signature ◽

Chromatin Accessibility ◽

Oesophageal Adenocarcinoma ◽

Cell Cycle Gene ◽

A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

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Gene Expression Patterns Underlying the Reinstatement of Plasticity in the Adult Visual System

Neural Plasticity ◽

10.1155/2013/605079 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Ettore Tiraboschi ◽

Ramon Guirado ◽

Dario Greco ◽

Petri Auvinen ◽

Jose Fernando Maya-Vetencourt ◽

...

Keyword(s):

Gene Expression ◽

Visual Cortex ◽

Large Scale ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Monocular Deprivation ◽

Adult Brain ◽

Gene Expression Patterns ◽

Postnatal Life ◽

Critical Periods

The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain.

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Trisomy 21 and Down syndrome: a short review

Brazilian Journal of Biology ◽

10.1590/s1519-69842008000200031 ◽

2008 ◽

Vol 68 (2) ◽

pp. 447-452 ◽

Cited By ~ 20

Author(s):

CA. Sommer ◽

F. Henrique-Silva

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Large Scale ◽

Molecular Mechanisms ◽

Global Gene Expression ◽

Short Review ◽

Complex Disorder ◽

Expression Studies ◽

Gene Expression Studies ◽

Chromosome Segments

Even though the molecular mechanisms underlying the Down syndrome (DS) phenotypes remain obscure, the characterization of the genes and conserved non-genic sequences of HSA21 together with large-scale gene expression studies in DS tissues are enhancing our understanding of this complex disorder. Also, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. Here we discuss the possible contribution of HSA21 genes to DS and data from global gene expression studies of trisomic samples.

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NETWORKS FROM GENE EXPRESSION TIME SERIES: CHARACTERIZATION OF CORRELATION PATTERNS

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127407018543 ◽

2007 ◽

Vol 17 (07) ◽

pp. 2477-2483 ◽

Cited By ~ 4

Author(s):

D. REMONDINI ◽

N. NERETTI ◽

C. FRANCESCHI ◽

P. TIERI ◽

J. M. SEDIVY ◽

...

Keyword(s):

Gene Expression ◽

Time Series ◽

Large Scale ◽

Molecular Mechanisms ◽

Single Gene ◽

Biological Information ◽

Reconstruction Method ◽

Gene Expression Time Series ◽

Expression Time

We address the problem of finding large-scale functional and structural relationships between genes, given a time series of gene expression data, namely mRNA concentration values measured from genetically engineered rat fibroblasts cell lines responding to conditional cMyc proto-oncogene activation. We show how it is possible to retrieve suitable information about molecular mechanisms governing the cell response to conditional perturbations. This task is complex because typical high-throughput genomics experiments are performed with high number of probesets (103–104 genes) and a limited number of observations (< 102 time points). In this paper, we develop a deepest analysis of our previous work [Remondini et al., 2005] in which we characterized some of the main features of a gene-gene interaction network reconstructed from temporal correlation of gene expression time series. One first advancement is based on the comparison of the reconstructed network with networks obtained from randomly generated data, in order to characterize which features retrieve real biological information, and which are instead due to the characteristics of the network reconstruction method. The second and perhaps more relevant advancement is the characterization of the global change in co-expression pattern following cMyc activation as compared to a basal unperturbed state. We propose an analogy with a physical system in a critical state close to a phase transition (e.g. Potts ferromagnet), since the cell responds to the stimulus with high susceptibility, such that a single gene activation propagates to almost the entire genome. Our result is relative to temporal properties of gene network dynamics, and there are experimental evidence that this can be related to spatial properties regarding the global organization of chromatine structure [Knoepfler et al., 2006].

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HOXB9 Is Overexpressed in Blast Cells from a Subset of Acute Myeloid Leukemia Patients and Supports Proliferation of AML Cell Lines.

Blood ◽

10.1182/blood.v104.11.65.65 ◽

2004 ◽

Vol 104 (11) ◽

pp. 65-65

Author(s):

Stefan Heinrichs ◽

Claudia Schoch ◽

Donna S. Neuberg ◽

A. Thomas Look

Keyword(s):

Gene Expression ◽

Cell Lines ◽

Molecular Mechanisms ◽

Hox Genes ◽

Rare Event ◽

Cellular Growth ◽

Hoxa Cluster ◽

Aberrant Expression ◽

Retroviral Transduction ◽

Myeloid Malignancies

Abstract Emerging evidence from studies in mice and humans suggests that HOX genes integrate the myelodysplastic and leukemogenic activities of different oncogenes. Translocations involving the MLL gene, a major upstream regulator of the HOXA cluster, have been identified in AML and define a specific cytogenetic subgroup of this disease. Recently, amplification of MLL was found in AML and MDS cases, revealing a second mechanism of deregulation of MLL and its downstream targets. However, additional leukemogenic upstream pathways have to be postulated, since upregulation of specific HOX genes, particularly HOXA9, is more frequent than MLL deregulation. Given the fact that HOXA9 is targeted by several yet to be identified mechanisms, we asked whether other members of the HOX9 paralog group are also highly expressed in myeloid malignancies. Our analysis of 449 AML patients by gene expression microarray revealed that besides HOXA9 (61% of all cases), HOXB9 is upregulated in 15% of the cases, whereas the overexpression of HOXC9 and HOXD9 expression is a very rare event (>1% of all cases). High levels of HOXB9 expression did not correlate with low levels of HOXA9 expression ruling out the possibility that HOXB9 compensates for a lack of HOXA9 activity in the leukemogenesis of a HOXA9 negative AML cases. Interestingly, within the cytogenetically defined subgroups (inv(16), t(15;17), t(8;21)) that have no HOXA9 expression at all, HOXB9 was also low or absent. To test if HOXB9 has the potential to contribute to the leukemogenic phenotype we analyzed a panel of human AML cell lines. The finding that 6 out of 24 cell lines express high levels of HOXB9 further indicates the significance of HOXB9 in myeloid malignancies. We chose K-562 and HEL as model cell lines since they express high levels of HOXB9, but lack HOXA9 expression. To reveal HOXB9 dependent pathways we designed two highly efficient siRNAs to target HOXB9 and knocked down its expression by retroviral transduction. In comparison to cells expressing a control siRNA, the resulting cell lines showed <5% of the control HOXB9 protein levels and a reduction in the cellular growth rate. Consequently, HOXB9 expression is required for the rapid growth of these AML cells. To gain insight into the molecular mechanisms underlying this phenotype we are performing global gene expression analysis. Preliminary results of our nearest neighbor analysis in K-562 cells revealed the upregulation of genes associated with erythroid differentiation upon HOXB9 knockdown. Our results indicate that HOXB9 expression inhibits the differentiation of leukemic myeloid progenitor cells, consistent with a role for the aberrant expression of this major HOX protein in leukemogenesis, by maintaining cells of the leukemic clone in an undifferentiated and rapidly proliferative state.

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Genomic dissection of the cytokine-controlled STAT5 signaling network in liver

Physiological Genomics ◽

10.1152/physiolgenomics.00048.2008 ◽

2008 ◽

Vol 34 (2) ◽

pp. 135-143 ◽

Cited By ~ 18

Author(s):

Atsushi Hosui ◽

Lothar Hennighausen

Keyword(s):

Gene Expression ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Target Genes ◽

Global Gene Expression ◽

Specific Expression ◽

Partial Explanation ◽

Downstream Target ◽

Expression Of Genes ◽

Global Gene Expression Profiling

Growth hormone (GH) controls the physiology and pathophysiology of the liver, and its signals are conducted by two members of the family of signal transducers and activators of transcription, STAT5A and STAT5B. Mice in which the Stat5a/b locus has been inactivated specifically in hepatocytes display GH resistance, the sex-specific expression of genes associated with liver metabolism and the cytochrome P-450 system is lost, and they develop hepatosteatosis. Several groups have shown by global gene expression profiling that a cadre of STAT5A/B target genes identify genetic cascades induced by GH and other cytokines. Evidence is accumulating that in the absence of STAT5A/B GH aberrantly activates STAT1 and STAT3 and their downstream target genes and thereby offers a partial explanation of some of the physiological alterations observed in Stat5a/b-null mice and human patients. We hypothesize that phenotypic changes observed in the absence of STAT5A/B are due to two distinct molecular consequences: first, the failure of STAT5A/B target genes to be activated by GH and second, the rerouting of GH signaling to other members of the STAT family. Rerouting of GH signaling to STAT1 and STAT3 might partially compensate for the loss of STAT5A/B, but it certainly activates biological programs distinct from STAT5A/B. Here we discuss the extent to which studies on global gene expression profiling have fostered a better understanding of the biology behind cytokine-STAT5A/B networks in hepatocytes. We also explore whether this wealth of information on gene activity can be used to further understand the roles of cytokines in liver disease.

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Gene Expression Analysis on the Early Development of Pig Embryos Exposed to Malathion

International Journal of Toxicology ◽

10.1080/10915810701226263 ◽

2007 ◽

Vol 26 (2) ◽

pp. 143-149 ◽

Cited By ~ 4

Author(s):

Zayil Salazar ◽

Yvonne Ducolomb ◽

Miguel Betancourt ◽

Edmundo Bonilla ◽

Leticia Cortés ◽

...

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Target Genes ◽

Hypothetical Protein ◽

Cdna Libraries ◽

Mhc I ◽

Vitro Fertilization ◽

Embryo Cells ◽

Gene Expression Alterations

Malathion is a widely used pesticide and there is evidence that it could alter mammal’s germ and somatic cells, as well as cell lines. There are not enough studies showing how the nonacute malathion doses affect gene expression. This study analyzes gene expression alterations in pig morular embryos exposed in vitro , for 96 h, to several malathion concentrations after in vitro fertilization. cDNA libraries of isolated morular embryos were created and differential screenings performed to identify target genes. Seven clones were certainly identified. Genes related to mitochondrial metabolism as cytochrome c subunits I and III, nuclear genes such as major histocompatibility complex I (MHC I), and a hypothetical protein related with a splicing factor were the target of malathion’s deregulation effect. The widespread use of malathion as a pesticide should be regarded with reproductive implications and more detailed analysis would yield more about molecular mechanisms of malathion injury on embryo cells.

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