scholarly journals Decision letter: Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism

2020 ◽  
Keyword(s):  
Gene Dose ◽  
Notch Gene

scholarly journals Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yi Kuang ◽  
Ohad Golan ◽  
Kristina Preusse ◽  
Brittany Cain ◽  
Collin J Christensen ◽  
...  
Keyword(s):  
Gene Dosage ◽  
Specific Binding ◽  
Notch Pathway ◽  
Signal Duration ◽  
Independent Manner ◽  
Gene Dose ◽  
Specific Binding Sites ◽  
Notch Gene ◽  
Pioneer Transcription Factor ◽  
Short Signal

Notch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we unexpectedly found that inserting an enhancer containing pioneer transcription factor sites coupled to Notch dimer sites can induce a subset of Notch haploinsufficiency phenotypes in Drosophila with wild type Notch gene dose. Using Drosophila genetics, we show that this enhancer induces Notch phenotypes in a Cdk8-dependent, transcription-independent manner. We further combined mathematical modeling with quantitative trait and expression analysis to build a model that describes how changes in Notch signal production versus degradation differentially impact cellular outcomes that require long versus short signal duration. Altogether, these findings support a ‘bind and discard’ mechanism in which enhancers with specific binding sites promote rapid Cdk8-dependent Notch turnover, and thereby reduce Notch-dependent transcription at other loci and sensitize tissues to gene dose based upon signal duration.

scholarly journals Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism

2019 ◽  
Author(s):  
Yi Kuang ◽  
Ohad Golan ◽  
Kristina Preusse ◽  
Brittany Cain ◽  
Joseph Salomone ◽  
...  
Keyword(s):  
Gene Dosage ◽  
Specific Binding ◽  
Notch Pathway ◽  
Independent Manner ◽  
Gene Dose ◽  
Specific Binding Sites ◽  
Long Duration ◽  
Notch Gene ◽  
Pioneer Transcription Factor ◽  
Variable Penetrance

SUMMARYNotch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we show that inserting a single enhancer containing pioneer transcription factor sites coupled to Notch dimer sites can unexpectedly induce a subset of Drosophila Notch haploinsufficiency phenotypes in an animal with wild type Notch gene dose. Mechanistically, this enhancer couples Notch DNA binding to degradation in a Cdk8-dependent, transcription-independent manner. Using mathematical modeling combined with quantitative trait and expression analysis, we show that tissues requiring long duration Notch signals are more sensitive to perturbations in Notch degradation compared to tissues relying upon short duration processes. These findings support a novel “bind and discard” mechanism in which enhancers with specific binding sites promote rapid Notch turnover, reduce Notch-dependent transcription at other loci, and thereby sensitize tissues to gene dose based upon signal duration.

scholarly journals Author response: Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism

2020 ◽  
Author(s):  
Yi Kuang ◽  
Ohad Golan ◽  
Kristina Preusse ◽  
Brittany Cain ◽  
Collin J Christensen ◽  
...  
Keyword(s):  
Author Response ◽  
Gene Dose ◽  
Notch Gene

glp-1 can substitute for lin-12 in specifying cell fate decisions in Caenorhabditis elegans

Development ◽  
1993 ◽  
Vol 119 (4) ◽  
pp. 1019-1027 ◽  
Author(s):  
K. Fitzgerald ◽  
H.A. Wilkinson ◽  
I. Greenwald
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Effector Proteins ◽  
Regulatory Sequences ◽  
Animal Kingdom ◽  
Cell Fate Decisions ◽  
Notch Gene ◽  
Epidermal Growth ◽  
Differential Gene ◽  
Mutant Phenotypes

Members of the lin-12/Notch gene family encode receptors for intercellular signals and are found throughout the animal kingdom. In many animals, the presence of at least two lin-12/Notch genes raises the issue of the significance of this duplication and divergence. In Caenorhabditis elegans, two lin-12/Notch genes, lin-12 and glp-1, encode proteins that are 50% identical, with different numbers of epidermal growth factor-like motifs in their extracellular domains. Many of the cell fate decisions mediated by lin-12 and glp-1 are distinct. Here, we express glp-1 protein under the control of lin-12 regulatory sequences in animals lacking endogenous lin-12 activity and find that glp-1 can substitute for lin-12 in mediating cell fate decisions. These results imply that the lin-12 and glp-1 proteins are biochemically interchangeable, sharing common ligand and effector proteins, and that the discrete lin-12 and glp-1 mutant phenotypes result from differential gene expression. In addition, these results suggest that the duplicate lin-12/Notch genes found in vertebrates may also be biochemically interchangeable.

Thebric à braclocus consists of two paralogous genes encoding BTB/POZ domain proteins and acts as a homeotic and morphogenetic regulator of imaginal development inDrosophila

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2419-2433 ◽  
Author(s):  
Jean-Louis Couderc ◽  
Dorothea Godt ◽  
Susan Zollman ◽  
Jiong Chen ◽  
Michelle Li ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Nuclear Protein ◽  
Drosophila Species ◽  
Sexually Dimorphic ◽  
Conserved Domains ◽  
Gene Dose ◽  
Highly Sensitive ◽  
Genes Encoding ◽  
Redundant Functions ◽  
Related Morphology

The bric à brac (bab) locus acts as a homeotic and morphogenetic regulator in the development of ovaries, appendages and the abdomen. It consists of two structurally and functionally related genes, bab1 and bab2, each of which encodes a single nuclear protein. Bab1 and Bab2 have two conserved domains in common, a BTB/POZ domain and a Psq domain, a motif that characterizes a subfamily of BTB/POZ domain proteins in Drosophila. The tissue distribution of Bab1 and Bab2 overlaps, with Bab1 being expressed in a subpattern of Bab2. Analysis of a series of mutations indicates that the two bab genes have synergistic, distinct and redundant functions during imaginal development. Interestingly, several reproduction-related traits that are sexually dimorphic or show diversity among Drosophila species are highly sensitive to changes in the bab gene dose, suggesting that alterations in bab activity may contribute to evolutionary modification of sex-related morphology.

scholarly journals Evolution of dosage compensation does not depend on genomic background

2020 ◽  
Author(s):  
Michail Rovatsos ◽  
Lukáš Kratochvíl
Keyword(s):  
Dosage Compensation ◽  
Sex Chromosomes ◽  
Sex Chromosome ◽  
Genomic Region ◽  
Gene Copy ◽  
Gene Dose ◽  
Copy Numbers ◽  
Compensation Mechanisms ◽  
Gene Copy Numbers ◽  
Softshell Turtles

AbstractOrganisms evolved various mechanisms to cope with the differences in the gene copy numbers between sexes caused by degeneration of Y and W sex chromosomes. Complete dosage compensation or at least expression balance between sexes was reported predominantly in XX/XY, but rarely in ZZ/ZW systems. However, this often-reported pattern is based on comparisons of lineages where sex chromosomes evolved from non-homologous genomic regions, potentially differing in sensitivity to differences in gene copy numbers. Here we document that two reptilian lineages (XX/XY iguanas and ZZ/ZW softshell turtles), which independently co-opted the same ancestral genomic region for the function of sex chromosomes, evolved different gene dose regulatory mechanisms. The independent co-option of the same genomic region for the role of sex chromosome as in the iguanas and the softshell turtles offers a great opportunity for testing evolutionary scenarios on the sex chromosome evolution under the explicit control for the genomic background and for gene identity. We showed that the parallel loss of functional genes from the Y chromosome of the green anole and the W chromosome of the Florida softshell turtle led to different dosage compensation mechanisms. Our approach controlling for genetic background thus does not support that the variability in the regulation of the gene dose differences is a consequence of ancestral autosomal gene content.

scholarly journals Do male and female heterogamety really differ in expression regulation? Lack of global dosage balance in pygopodid geckos

2021 ◽  
Vol 376 (1833) ◽  
pp. 20200102 ◽  
Author(s):  
Michail Rovatsos ◽  
Tony Gamble ◽  
Stuart V. Nielsen ◽  
Arthur Georges ◽  
Tariq Ezaz ◽  
...  
Keyword(s):  
Sex Determination ◽  
Sex Chromosomes ◽  
Gene Dosage ◽  
Regulatory Mechanisms ◽  
Gene Copy ◽  
Male And Female ◽  
Gene Dose ◽  
Female Heterogamety ◽  
Dosage Balance ◽  
Male Heterogamety

Differentiation of sex chromosomes is thought to have evolved with cessation of recombination and subsequent loss of genes from the degenerated partner (Y and W) of sex chromosomes, which in turn leads to imbalance of gene dosage between sexes. Based on work with traditional model species, theory suggests that unequal gene copy numbers lead to the evolution of mechanisms to counter this imbalance. Dosage compensation, or at least achieving dosage balance in expression of sex-linked genes between sexes, has largely been documented in lineages with male heterogamety (XX/XY sex determination), while ZZ/ZW systems are assumed to be usually associated with the lack of chromosome-wide gene dose regulatory mechanisms. Here, we document that although the pygopodid geckos evolved male heterogamety with a degenerated Y chromosome 32–72 Ma, one species in particular, Burton's legless lizard ( Lialis burtonis ), does not possess dosage balance in the expression of genes in its X-specific region. We summarize studies on gene dose regulatory mechanisms in animals and conclude that there is in them no significant dichotomy between male and female heterogamety. We speculate that gene dose regulatory mechanisms are likely to be related to the general mechanisms of sex determination instead of type of heterogamety. This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part II)’.

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