scholarly journals The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization

2018 ◽  
Author(s):  
Pedro Prudêncio ◽  
Leonardo G. Guilgur ◽  
João Sobral ◽  
Jörg D. Becker ◽  
Rui Gonçalo Martinho ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Transcriptional Program ◽  
Gene Subset ◽  
Paternal Genome ◽  
Trithorax Group ◽  
Evolutionarily Conserved ◽  
Group Protein ◽  
Oocyte Differentiation ◽  
Zygotic Genome

ABSTRACTThe transition from fertilized oocyte to totipotent embryo relies on maternally-provided factors that are synthetized and accumulated in developing oocytes. Yet, it is still unclear how oocytes regulate the expression of these embryo fate-promoting genes within the general transcriptional program of oogenesis. Here we report that the Drosophila Trithorax group protein MLL3/4 (dMLL3/4, also known as Trr) is essential for the transition to embryo fate at fertilization. In the absence of dMLL3/4, oocytes develop normally but fail to initiate the embryo mitotic divisions after fertilization. This incapability results from defects in both paternal genome reprogramming and maternal meiotic completion. We show that, during oogenesis, dMLL3/4 promotes the expression of a functionally coherent gene subset that is later required for the correct assembly of the zygotic genome. Accordingly, we identify the evolutionarily-conserved IDGF4 glycoprotein (known as oviductin in mammals) as a new oocyte-to-embryo transition gene under dMLL3/4 transcriptional control. Based on these observations, we propose that dMLL3/4 plays an instructive role in the oocyte-to-embryo transition that is functionally uncoupled from the requirements of normal oocyte differentiation.

scholarly journals The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization

EMBO Reports ◽  
2018 ◽  
Vol 19 (8) ◽  
Author(s):  
Pedro Prudêncio ◽  
Leonardo G Guilgur ◽  
João Sobral ◽  
Jörg D Becker ◽  
Rui Gonçalo Martinho ◽  
...  
Keyword(s):  
Trithorax Group ◽  
Group Protein ◽  
Zygotic Genome

scholarly journals The Trithorax group protein ASH1 requires a combination of BAH domain and AT hooks, but not the SET domain, for mitotic chromatin binding and survival

Chromosoma ◽  
2021 ◽  
Author(s):  
Philipp A. Steffen ◽  
Christina Altmutter ◽  
Eva Dworschak ◽  
Sini Junttila ◽  
Attila Gyenesei ◽  
...  
Keyword(s):  
Transcriptional Profiling ◽  
Histone H3 ◽  
Chromatin Binding ◽  
Set Domain ◽  
Trithorax Group ◽  
Trxg Protein ◽  
Group Protein ◽  
Bah Domain ◽  
Mitotic Chromatin

AbstractThe Drosophila Trithorax group (TrxG) protein ASH1 remains associated with mitotic chromatin through mechanisms that are poorly understood. ASH1 dimethylates histone H3 at lysine 36 via its SET domain. Here, we identify domains of the TrxG protein ASH1 that are required for mitotic chromatin attachment in living Drosophila. Quantitative live imaging demonstrates that ASH1 requires AT hooks and the BAH domain but not the SET domain for full chromatin binding in metaphase, and that none of these domains are essential for interphase binding. Genetic experiments show that disruptions of the AT hooks and the BAH domain together, but not deletion of the SET domain alone, are lethal. Transcriptional profiling demonstrates that intact ASH1 AT hooks and the BAH domain are required to maintain expression levels of a specific set of genes, including several involved in cell identity and survival. This study identifies in vivo roles for specific ASH1 domains in mitotic binding, gene regulation, and survival that are distinct from its functions as a histone methyltransferase.

scholarly journals Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 4034-4046 ◽  
Author(s):  
Giuseppe Zardo ◽  
Alberto Ciolfi ◽  
Laura Vian ◽  
Linda M. Starnes ◽  
Monia Billi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Transcriptional Control ◽  
Transcriptional Level ◽  
Seed Region ◽  
Mrna Targets ◽  
Epigenetic Events ◽  
Evolutionarily Conserved ◽  
Lineage Decision ◽  
Chromatin Remodeling Complexes

Abstract Epigenetic modifications regulate developmental genes involved in stem cell identity and lineage choice. NFI-A is a posttranscriptional microRNA-223 (miR-223) target directing human hematopoietic progenitor lineage decision: NFI-A induction or silencing boosts erythropoiesis or granulopoiesis, respectively. Here we show that NFI-A promoter silencing, which allows granulopoiesis, is guaranteed by epigenetic events, including the resolution of opposing chromatin “bivalent domains,” hypermethylation, recruitment of polycomb (PcG)–RNAi complexes, and miR-223 promoter targeting activity. During granulopoiesis, miR-223 localizes inside the nucleus and targets the NFI-A promoter region containing PcGs binding sites and miR-223 complementary DNA sequences, evolutionarily conserved in mammalians. Remarkably, both the integrity of the PcGs-RNAi complex and DNA sequences matching the seed region of miR-223 are required to induce NFI-A transcriptional silencing. Moreover, ectopic miR-223 expression in human myeloid progenitors causes heterochromatic repression of NFI-A gene and channels granulopoiesis, whereas its stable knockdown produces the opposite effects. Our findings indicate that, besides the regulation of translation of mRNA targets, endogenous miRs can affect gene expression at the transcriptional level, functioning in a critical interface between chromatin remodeling complexes and the genome to direct fate lineage determination of hematopoietic progenitors.

scholarly journals A developmentally programmed splicing failure attenuates the DNA damage response during mammalian zygotic genome activation

2020 ◽  
Author(s):  
Christopher D. R. Wyatt ◽  
Barbara Pernaute ◽  
André Gohr ◽  
Marta Miret-Cuesta ◽  
Lucia Goyeneche ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Transcriptional Control ◽  
Exon Skipping ◽  
Tissue Type ◽  
Zygotic Genome Activation ◽  
Damage Response ◽  
Mammalian Embryos ◽  
Genome Activation ◽  
Zygotic Genome

ABSTRACTThe transition from maternal to embryonic transcriptional control is a crucial step in embryogenesis. However, how alternative splicing is regulated during this process and how it contributes to early development is unknown. Using transcriptomic data from pre-implantation stages of human, mouse and cow, we show that the stage of zygotic genome activation (ZGA) exhibits the highest levels of exon skipping diversity reported for any cell or tissue type. Interestingly, much of this exon skipping is temporary, leads to disruptive non-canonical isoforms, and occurs in genes enriched for DNA damage response in the three species. We identified two core spliceosomal components, Snrpb and Snrpd2, as regulators of these patterns. These genes have low maternal expression at the time of ZGA and increase sharply thereafter. Consistently, microinjection of Snrpb/d2 mRNA into mouse zygotes reduces the levels of temporary exon skipping at ZGA, and leads to an increase in etoposide-induced DNA damage response. Altogether, our results suggest that mammalian embryos undergo an evolutionarily conserved and developmentally programmed specific splicing failure at the time of genome activation that attenuates cellular responses to DNA damage at these early stages.

NUP98-MLL fusion in human acute myeloblastic leukemia

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2332-2335 ◽  
Author(s):  
Sophie Kaltenbach ◽  
Gwendoline Soler ◽  
Carole Barin ◽  
Carine Gervais ◽  
Olivier A. Bernard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fusion Protein ◽  
Histone H3 ◽  
Cellular Transformation ◽  
Human Leukemia ◽  
Trithorax Group ◽  
Group Protein ◽  
Hoxa Genes ◽  
Hoxa Gene Expression ◽  
Methylation Activity

Abstract Posttranscriptional modifications of histones play important roles in the control of chromatin structure and transcription. H3K4 (histone H3 lysine 4) methylation by the SET domain of the trithorax-group protein MLL (mixed-lineage leukemia) is important for the control of homeobox (HOX) gene expression during development. MLL is tethered to the HOXA locus through interaction of its amino-terminus with menin. MLL fusion proteins associated with human leukemia contain the menin interaction peptide and frequently recruit H3K79 (histone H3 lysine 79) methylation activity. This allows sustained expression of HOXA genes important for cellular transformation. We have characterized a novel recurrent chromosomal aberration, inv(11)(p15q23), as an isolated chromosomal abnormality in 2 patients with acute myeloid leukemia. This aberration is predicted to result in the expression of an NUP98 (nucleoporin 98 kDa)–MLL fusion protein that is unable to interact with menin. As expected, low levels of HOXA gene expression were observed in the patients' samples. This fusion protein is predicted to participate in cellular transformation by activating MLL targets other than HOXA genes.

scholarly journals Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain

2011 ◽  
Vol 18 (7) ◽  
pp. 857-859 ◽  
Author(s):  
Sabina Sarvan ◽  
Vanja Avdic ◽  
Véronique Tremblay ◽  
Chandra-Prakash Chaturvedi ◽  
Pamela Zhang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Dna Binding ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Trithorax Group ◽  
Group Protein

The Drosophila kismet gene is related to chromatin-remodeling factors and is required for both segmentation and segment identity

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1175-1187 ◽  
Author(s):  
G. Daubresse ◽  
R. Deuring ◽  
L. Moore ◽  
O. Papoulas ◽  
I. Zakrajsek ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Homeotic Genes ◽  
Loss Of Function ◽  
Larval Body ◽  
Sex Combs Reduced ◽  
Trithorax Group ◽  
Sex Combs ◽  
Pair Rule Gene ◽  
Body Segmentation ◽  
Group Protein

The Drosophila kismet gene was identified in a screen for dominant suppressors of Polycomb, a repressor of homeotic genes. Here we show that kismet mutations suppress the Polycomb mutant phenotype by blocking the ectopic transcription of homeotic genes. Loss of zygotic kismet function causes homeotic transformations similar to those associated with loss-of-function mutations in the homeotic genes Sex combs reduced and Abdominal-B. kismet is also required for proper larval body segmentation. Loss of maternal kismet function causes segmentation defects similar to those caused by mutations in the pair-rule gene even-skipped. The kismet gene encodes several large nuclear proteins that are ubiquitously expressed along the anterior-posterior axis. The Kismet proteins contain a domain conserved in the trithorax group protein Brahma and related chromatin-remodeling factors, providing further evidence that alterations in chromatin structure are required to maintain the spatially restricted patterns of homeotic gene transcription.

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