scholarly journals Independent origin of MIRNA genes controlling homologous target genes by partial inverted duplication of antisense-transcribed sequences

2019 ◽  
Author(s):  
Lydia Gramzow ◽  
Dajana Lobbes ◽  
Sophia Walter ◽  
Nathan Innard ◽  
Günter Theißen
Keyword(s):  
Transcription Factors ◽  
Target Gene ◽  
Target Genes ◽  
Mirna Biogenesis ◽  
Mads Box ◽  
Mads Box Genes ◽  
Developmental Processes ◽  
Inverted Duplication ◽  
The Future ◽  
Transcribed Sequences

AbstractSome microRNAs (miRNAs) are key regulators of developmental processes, mainly by controlling the accumulation of transcripts encoding transcription factors that are important for morphogenesis. MADS-box genes encode a family of transcription factors which control diverse developmental processes in flowering plants. Here we study the convergent evolution of two MIRNA (MIR) gene families, named MIR444 and MIR824, targeting members of the same clade of MIKCC-group MADS-box genes. We show that these two MIR genes most likely originated independently in monocots (MIR444) and in Brassicales (eudicots, MIR824). We provide evidence that in both cases the future target gene was transcribed in antisense prior to the evolution of the MIR genes. Both MIR genes then likely originated by a partial inverted duplication of their target genes, resulting in natural antisense organization of the newly evolved MIR gene and its target gene at birth. We thus propose a new model for the origin of MIR genes, MEPIDAS (MicroRNA Evolution by Partial Inverted Duplication of Antisense-transcribed Sequences). MEPIDAS is a refinement of the inverted duplication hypothesis. According to MEPIDAS, a MIR gene evolves at a genomic locus at which the future target gene is also transcribed in the antisense direction. A partial inverted duplication at this locus causes the antisense transcript to fold into a stem-loop structure that is recognized by the miRNA biogenesis machinery to produce a miRNA that regulates the gene at this locus. Our analyses exemplify how to elucidate the origin of conserved miRNAs by comparative genomics and will guide future studies.

scholarly journals Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity

2020 ◽  
Vol 21 (24) ◽  
pp. 9401
Author(s):  
Antonio Bouthelier ◽  
Florinda Meléndez-Rodríguez ◽  
Andrés A. Urrutia ◽  
Julián Aragonés
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Cellular Response ◽  
Target Gene ◽  
Target Genes ◽  
Transactivation Domain ◽  
Transactivation Domains ◽  
Relative Contribution

Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional Vhl-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as CAIX (CAR9) and BNIP3, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier SLC7A5. The HIF selectivity for some genes in WT8 cells is conserved in Vhl-deficient lung and liver tissue, whereas other genes like Glut1 (Slc2a1) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed.

FLT3ITD Target Enhancers Are Primed but Inaccessible in Fetal Hematopoietic Progenitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1228-1228
Author(s):  
Yanan Li ◽  
Riddhi M Patel ◽  
Emily Casey ◽  
Jeffrey A. Magee
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Target Gene ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Gene Activation ◽  
Chromatin Accessibility ◽  
Luciferase Reporter ◽  
Enhancer Activity ◽  
Target Gene Expression

The FLT3 Internal Tandem Duplication (FLT3ITD) is common somatic mutation in acute myeloid leukemia (AML). We have previously shown that FLT3ITD fails to induce changes in HSC self-renewal, myelopoiesis and leukemogenesis during fetal stages of life. FLT3ITD signal transduction pathways are hyperactivated in fetal progenitors, but FLT3ITD target genes are not. This suggests that postnatal-specific transcription factors may be required to help induce FLT3ITD target gene expression. Alternatively, repressive histone modifications may impose a barrier to FLT3ITD target gene activation in fetal HPCs that is relaxed during postnatal development. To resolve these possibilities, we used ATAC-seq, as well as H3K4me1, H3K27ac and H3K27me3 ChIP-seq, to identify cis-elements that putatively control FLT3ITD target gene expression in fetal and adult hematopoietic progenitor cells (HPCs). We identified many enhancer elements (ATAC-seq peaks with H3K4me1 and H3K27ac) that exhibited increased chromatin accessibility and activity in FLT3ITD adult HPCs relative to wild type adult HPCs. These elements were enriched near FLT3ITD target genes. HOMER analysis showed enrichment for STAT5, ETS, RUNX1 and IRF binding motifs within the FLT3ITD target enhancers, but motifs for temporally dynamic transcription factors were not identified. We cloned a subset of the enhancers and confirmed that they could synergize with their promoter to activate a luciferase reporter. For representative enhancers, STAT5 binding sites were required to activate the enhancer - as anticipated - and RUNX1 repressed enhancer activity. We tested whether accessibility or priming changed between fetal and adult stages of HPC development. FLT3ITD-dependent changes in chromatin accessibility were not observed in fetal HPCs, though the enhancers were primed early in development as evidenced by the presence of H3K4me1. Repressive H3K27me3 were not present at FLT3ITD target enhancers in either or adult HPCs. The data show that FLT3ITD target enhancers are demarcated early in hematopoietic development, long before they become responsive to FLT3ITD signaling. Repressive marks do not appear to create an epigenetic barrier to enhancer activation in the fetal stage. Instead, age-specific transcription factors are likely required to pioneer enhancer elements so that they can respond to STAT5 and other FLT3ITD effectors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hey Basic Helix-Loop-Helix Transcription Factors Are Repressors of GATA4 and GATA6 and Restrict Expression of the GATA Target Gene ANF in Fetal Hearts

2005 ◽  
Vol 25 (20) ◽  
pp. 8960-8970 ◽  
Author(s):  
Andreas Fischer ◽  
Jürgen Klattig ◽  
Burkhard Kneitz ◽  
Holger Diez ◽  
Manfred Maier ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Lines ◽  
Target Gene ◽  
Target Genes ◽  
Heart Defects ◽  
Embryonic Stem ◽  
Embryoid Bodies ◽  
Mrna Levels ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix

ABSTRACT The Hey basic helix-loop-helix transcription factors are downstream effectors of Notch signaling in the cardiovascular system. Mice lacking Hey2 develop cardiac hypertrophy, often associated with congenital heart defects, whereas combined Hey1/Hey2 deficiency leads to severe vascular defects and embryonic lethality around embryonic day E9.5. The molecular basis of these disorders is poorly understood, however, since target genes of Hey transcription factors in the affected tissues remain elusive. To identify genes regulated by Hey factors we have generated a conditional Hey1 knockout mouse. This strain was used to generate paired Hey2- and Hey1/2-deficient embryonic stem cell lines. Comparison of these cell lines by microarray analysis identified GATA4 and GATA6 as differentially expressed genes. Loss of Hey1/2 leads to elevated GATA4/6 and ANF mRNA levels in embryoid bodies, while forced expression of Hey factors strongly represses expression of the GATA4 and GATA6 promoter in various cell lines. In addition, the promoter activity of the GATA4/6 target gene ANF was inhibited by Hey1, Hey2, and HeyL. Protein interaction and mutation analyses suggest that repression is due to direct binding of Hey proteins to GATA4 and GATA6, blocking their transcriptional activity. In Hey2-deficient fetal hearts we observed elevated mRNA levels of ANF and CARP. Expression of ANF and Hey2 is normally restricted to the trabecular and compact myocardial layer, respectively. Intriguingly, loss of Hey2 leads to ectopic ANF expression in the compact layer, suggesting a direct role for Hey2 in limiting ANF expression in this cardiac compartment.

scholarly journals Evolutionary divergence of motifs in B-class MADS-box proteins of seed plants

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Gangxu Shen ◽  
Yong Jia ◽  
Wei-Lung Wang
Keyword(s):  
Transcription Factors ◽  
Functional Divergence ◽  
Acid Sites ◽  
Evolutionary Divergence ◽  
Alternative Mechanism ◽  
Sequence Motifs ◽  
Mads Box ◽  
Mads Box Genes ◽  
Systematic Analysis ◽  
Conserved Sequence

Abstract Background MADS-box transcription factors function as homo- or heterodimers and regulate many aspects of plant development; moreover, MADS-box genes have undergone extensive duplication and divergence. For example, the morphological diversity of floral organs is closely related to the functional divergence of the MADS-box gene family. B-class genes (such as Arabidopsis thaliana APETALA3 [AP3] and PISTILLATA [PI]) belong to a subgroup of MADS-box genes. Here, we collected 97 MADS-box B protein sequences from 21 seed plant species and examined their motifs to better understand the functional evolution of B proteins. Results We used the MEME tool to identify conserved sequence motifs in these B proteins; unique motif arrangements and sequences were identified in these B proteins. The keratin-like domains of Malus domestica and Populus trichocarpa B proteins differed from those in other angiosperms, suggesting that a novel regulatory network might have evolved in these species. The MADS domains of Nelumbo nucifera, Glycine max, and Amborella trichopoda B-proteins contained motif 9; in contrast, those of other plants contained motif 1. Protein modelling analyses revealed that MADS domains with motif 9 may lack amino acid sites required for DNA-binding. These results suggested that the three species might share an alternative mechanism controlling floral development. Conclusions Amborella trichopoda has B proteins with either motif 1 or motif 9 MADS domains, suggesting that these two types of MADS domains evolved from the ancestral domain into two groups, those with motif 9 (N. nucifera and G. max), and those with motif 1. Moreover, our results suggest that the homodimer/heterodimer intermediate transition structure first appeared in A. trichopoda. Therefore, our systematic analysis of the motifs in B proteins sheds light on the evolution of these important transcription factors.

scholarly journals Decoding transcriptional regulation via a human gene expression predictor

2020 ◽  
Author(s):  
Yuzhou Wang ◽  
Yu Zhang ◽  
Jiazhen Gong ◽  
Jianqiang Bao ◽  
Shisong Ma
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Stress Response ◽  
Target Gene ◽  
Target Genes ◽  
Human Gene ◽  
Human Gene Expression ◽  
Novel Approach ◽  
Wide Range

ABSTRACTTranscription factors (TF) regulate cellular activities via controlling gene expression, but a predictive model describing how TFs quantitatively modulate human transcriptomes was lacking. We constructed a universal human gene expression predictor and utilized it to decode transcriptional regulation. Using 1613 TFs’ expression, the predictor reconstituted highly accurate transcriptomes for samples derived from a wide range of tissues and conditions. The predictor’s broad applicability indicated it had recapitulated the quantitative relationships between TFs and target genes ubiquitous across tissues. Significant interacting TF-target gene pairs were then extracted from the predictor and enabled downstream inference of TF regulators for diverse pathways involved in development, immunity, metabolism, and stress response. Thus, we present a novel approach to study human transcriptional regulation following the “understanding by modeling” principle.

Mechanisms regulating target gene selection by the homeodomain-containing protein Fushi tarazu

Development ◽  
2000 ◽  
Vol 127 (13) ◽  
pp. 2965-2976 ◽  
Author(s):  
A. Nasiadka ◽  
A. Grill ◽  
H.M. Krause
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Site ◽  
Target Gene ◽  
Target Genes ◽  
Gene Selection ◽  
Activity Regulation ◽  
Fushi Tarazu ◽  
Activation Domain ◽  
Regulation Model

Homeodomain proteins are DNA-binding transcription factors that control major developmental patterning events. Although DNA binding is mediated by the homeodomain, interactions with other transcription factors play an unusually important role in the selection and regulation of target genes. A major question in the field is whether these cofactor interactions select target genes by modulating DNA binding site specificity (selective binding model), transcriptional activity (activity regulation model) or both. A related issue is whether the number of target genes bound and regulated is a small or large percentage of genes in the genome. In this study, we have addressed these issues using a chimeric protein that contains the strong activation domain of the viral VP16 protein fused to the Drosophila homeodomain-containing protein Fushi tarazu (Ftz). We find that genes previously thought not to be direct targets of Ftz remain unaffected by FtzVP16. Addition of the VP16 activation domain to Ftz does, however, allow it to regulate previously identified target genes at times and in regions that Ftz alone cannot. It also changes Ftz into an activator of two genes that it normally represses. Taken together, the results suggest that Ftz binds and regulates a relatively limited number of target genes, and that cofactors affect target gene specificity primarily by controlling binding site selection. Activity regulation then fine-tunes the temporal and spatial domains of promoter responses, the magnitude of these responses, and whether they are positive or negative.

scholarly journals Genome-wide identification of MADS-box gene family in sacred lotus (Nelumbo nucifera) identifies a SEPALLATA homolog gene involved in floral development

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhongyuan Lin ◽  
Dingding Cao ◽  
Rebecca Njeri Damaris ◽  
Pingfang Yang
Keyword(s):  
Transcription Factors ◽  
Gene Family ◽  
Flower Development ◽  
Nelumbo Nucifera ◽  
Mads Box ◽  
Mads Box Genes ◽  
Floral Organogenesis ◽  
Sacred Lotus ◽  
Lotus Flower ◽  
Mads Box Gene

Abstract Background Sacred lotus (Nelumbo nucifera) is a vital perennial aquatic ornamental plant. Its flower shape determines the horticultural and ornamental values. However, the mechanisms underlying lotus flower development are still elusive. MADS-box transcription factors are crucial in various features of plant development, especially in floral organogenesis and specification. It is still unknown how the MADS-box transcription factors regulate the floral organogenesis in lotus. Results To obtain a comprehensive insight into the functions of MADS-box genes in sacred lotus flower development, we systematically characterized members of this gene family based on the available genome information. A total of 44 MADS-box genes were identified, of which 16 type I and 28 type II genes were categorized based on the phylogenetic analysis. Furthermore, the structure of MADS-box genes and their expressional patterns were also systematically analyzed. Additionally, subcellular localization analysis showed that they are mainly localized in the nucleus, of which a SEPALLATA3 (SEP3) homolog NnMADS14 was proven to be involved in the floral organogenesis. Conclusion These results provide some fundamental information about the MADS-box gene family and their functions, which might be helpful in not only understanding the mechanisms of floral organogenesis but also breeding of high ornamental value cultivars in lotus.

Regulation of Myelopoiesis by Differentiation Stage-Specific Activities of HOXA9 and HOXA10

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-29-SCI-29
Author(s):  
Elizabeth A. Eklund
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
Gene Networks ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Murine Bone Marrow

Abstract Abstract SCI-29 HOXA9 and HOXA10 are homeodomain (HD) transcription factors that are implicated in control of myelopoiesis and contribute to myeloid leukemogenesis. These proteins are expressed coordinately during hematopoiesis, with maximal expression in granulocyte/monocyte progenitor (GMP) cells. Engineered overexpression of Hoxa9 or Hoxa10 in primary bone marrow cells expands the GMP population in vitro, and results in myeloproliferation in murine bone marrow transplant experiments. Mice transplanted with Hoxa9- or Hoxa10-overexpressing bone marrow develop acute myeloid leukemia (AML) over time. Consistent with this, increased and sustained expression of a set of HD proteins, including HOXA9 and HOXA10, is found in a subset of human AML, including AML with MLL gene translocations (11q23-AML). Since the DNA-binding HDs of HOXA9 and HOXA10 are highly conserved, we hypothesize that they recognize a common set of target genes. However, since HOXA9 and HOXA10 diverge outside the HD, we considered the unexplored possibility that they perform different functions in regulating such genes. To identify molecular mechanisms for HOX-induced GMP expansion and leukemogenesis, we performed a chromatin immunoprecipitation-based screen for HOXA10 target genes. Gene ontology studies determined that the identified set is enriched for genes encoding growth factors and receptors, including fibroblast growth factor 2 (FGF2). We found that production of FGF2 by Hoxa10-overexpressing GMP stabilizes β-catenin and induces proliferation in an autocrine manner. We also found that HOXA9 and HOXA10 activate common FGF2 cis elements. The Hoxa10-target-gene set is also enriched for HD-transcription factors, including CDX4. We determined that Cdx4 transcription is activated by HOXA10 in GMP, but repressed by HOXA9 in differentiating myeloid cells. CDX4 activates transcription of both Hoxa9 and Hoxa10, identifying a HOX-CDX cross-regulatory mechanism. This mechanism may be influenced by Fgf2, since Hoxa10 and Cdx4 are β-catenin target genes, but β-catenin activity decreases Hoxa9 expression. Gene expression profiling studies indicate that HOXA9, HOXA10, CDX4, and FGF2 are increased in 11q23-AML, suggesting clinical relevance. Arih2 (encoding the E3 ligase Triad1) is another common HOXA9 and HOXA10 target gene that may influence Fgf2 activity. We found that Arih2 transcription is repressed by HOXA9 in myeloid progenitors, but activated by HOXA10 in differentiating phagocytes. FGF receptors are destabilized by ubiquitination, and we found increased FGF-R ubiquitination in Hoxa10-overexpressing cells. Therefore, Triad1-dependent regulation of FGF-R stability is another mechanism for control of FGF2 activity and myeloproliferation by HOXA9 and HOXA10. Therefore, HOXA9 and HOXA10 regulate a common set of target genes that control GMP expansion in a manner that is antagonistic for some genes and cooperative for others. Clinical correlative studies suggest that coordinate control of these genes by HOXA9 and HOXA10 is dysregulated in HOX-overexpressing leukemia. Understanding HOX-regulated gene networks may identify therapeutic targets for HOX-overexpressing leukemias. For example, blocking FGF-related signaling pathways may ameliorate cytokine hypersensitivity in such leukemias, and would be a topic of interest for additional studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals midline represses Dpp signaling and target gene expression in Drosophila ventral leg development

2021 ◽  
Author(s):  
Lindsay A. Phillips ◽  
Markle L. Atienza ◽  
Jae-Ryeon Ryu ◽  
Pia C. Svendsen ◽  
Lynn K. Kelemen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Dna Sequence ◽  
Target Gene ◽  
Target Genes ◽  
T Box ◽  
Leg Development ◽  
Summary Statement

AbstractVentral leg patterning in Drosophila is controlled by the expression of the redundant T-box Transcription factors midline (mid) and H15. Here we show that mid represses the Dpp-activated gene Daughters against decapentaplegic (Dad) through a consensus TBE site in the minimal enhancer, Dad13. Mutating the Dad13 DNA sequence results in an increased and broadening of Dad expression. We further demonstrate that the engrailed-homology-1 domain of Mid is critical for regulating the levels of phospho-Mad, a transducer of Dpp-signaling. However, we find that mid does not affect all Dpp-target genes as we demonstrate that brinker (brk) expression is unresponsive to mid. This study further illuminates the interplay between mechanisms involved in determination of cellular fate and the varied roles of mid.Summary statementVentral patterning is controlled in part by the T-box Transcription factor midline blocking Dpp signaling and Dpp-activated genes, though midline does not affect the Dpp-repressed gene brk.

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