Elk1 in congenital and late onset heart disease: at the heart of the matter

Jeanette Hallab, Romaric Bouveret, Gonzalo del Monte Nieto, Daniel Hesselson, Lee B. Miles, Sebastian Dworkin, Richard Harvey, Mirana Ramialison

Research output: Contribution to conferenceAbstractOtherpeer-review

Abstract

Elk1 is an ETS Class I, TCF subfamily transcription factor known as a well established downstream effector of the MAPK pathway and implicated in the causation of a variety of cancers. Recent in-vitro evidence places Elk1 and the other TCFs in the context of the cardiogenic transcription factor network but the in-vivo role of the TCFs in cardiogenesis remains unexplored.

Here, we provide the first in-vivo evidence of the role of the Elk1 in cardiogenesis using a zebrafish mutant with disrupted DNA binding domain (elk1-543/-543) and cardiac defects, including valve displacement/elongation and hypertrophic/hyperplastic changes. elk1-543/-543 are predisposed to early embryonic death, with high incidence of heart looping defects and accelerated growth among survivors.

RNA-sequencing (RNA-seq) at 6dpf provides insights into the basis of anatomical defects, with upregulation of MAPK components and downregulation of trim63a, encoding a homeostatic protein involved in reducing muscle mass, downregulation of which is associated with Hypertrophic Cardiomyopathy (HCM) in humans.

The inverse relationship between MAPK components and Trim63a is well-described although its fundamental basis is unknown. Here we provide the first mechanistic insight into this relationship, indicating that MAPK perturbations likely converge via the TCFs at the trim63a promoter, downregulating trim63a to mediate HCM.

RNA-seq at the tail bud stage has allowed us to identify putative, genomically hard-wired compensation mechanisms whereby loss of TCF function causes downregulation of tumor suppressor genes. We hypothesize this promotes proliferation and embryonic survival via non-optimal (compensatory) pathways, and is the fundamental mechanism underlying observed phenotypic defects.

The sum of anatomical and molecular changes observed in elk1-543/-543 mimic a group of congenital syndromes known as “RASopathies” in humans. Overall, our data provides high resolution insights into the time line of molecular events underlying RASopathies/MAPK pathway defects and their relationship to molecules imperative in heart patterning and homeostasis.
Original languageEnglish
PagesS30
Number of pages1
DOIs
Publication statusPublished - Jul 2017
Event18th International Congress of Developmental Biology - National University of Singapore, Singapore, Singapore
Duration: 18 Jun 201722 Jun 2017
Conference number: 18th
http://isdb2017.com/

Conference

Conference18th International Congress of Developmental Biology
Abbreviated titleISDB2017
CountrySingapore
CitySingapore
Period18/06/1722/06/17
Internet address

Cite this

Hallab, J., Bouveret, R., del Monte Nieto, G., Hesselson, D., Miles, L. B., Dworkin, S., ... Ramialison, M. (2017). Elk1 in congenital and late onset heart disease: at the heart of the matter. S30. Abstract from 18th International Congress of Developmental Biology, Singapore, Singapore. https://doi.org/10.1016/j.mod.2017.04.027
Hallab, Jeanette ; Bouveret, Romaric ; del Monte Nieto, Gonzalo ; Hesselson, Daniel ; Miles, Lee B. ; Dworkin, Sebastian ; Harvey, Richard ; Ramialison, Mirana. / Elk1 in congenital and late onset heart disease: at the heart of the matter. Abstract from 18th International Congress of Developmental Biology, Singapore, Singapore.1 p.
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Hallab, J, Bouveret, R, del Monte Nieto, G, Hesselson, D, Miles, LB, Dworkin, S, Harvey, R & Ramialison, M 2017, 'Elk1 in congenital and late onset heart disease: at the heart of the matter' 18th International Congress of Developmental Biology, Singapore, Singapore, 18/06/17 - 22/06/17, pp. S30. https://doi.org/10.1016/j.mod.2017.04.027

Elk1 in congenital and late onset heart disease: at the heart of the matter. / Hallab, Jeanette; Bouveret, Romaric; del Monte Nieto, Gonzalo; Hesselson, Daniel; Miles, Lee B.; Dworkin, Sebastian; Harvey, Richard; Ramialison, Mirana.

2017. S30 Abstract from 18th International Congress of Developmental Biology, Singapore, Singapore.

Research output: Contribution to conferenceAbstractOtherpeer-review

TY - CONF

T1 - Elk1 in congenital and late onset heart disease: at the heart of the matter

AU - Hallab, Jeanette

AU - Bouveret, Romaric

AU - del Monte Nieto, Gonzalo

AU - Hesselson, Daniel

AU - Miles, Lee B.

AU - Dworkin, Sebastian

AU - Harvey, Richard

AU - Ramialison, Mirana

PY - 2017/7

Y1 - 2017/7

N2 - Elk1 is an ETS Class I, TCF subfamily transcription factor known as a well established downstream effector of the MAPK pathway and implicated in the causation of a variety of cancers. Recent in-vitro evidence places Elk1 and the other TCFs in the context of the cardiogenic transcription factor network but the in-vivo role of the TCFs in cardiogenesis remains unexplored.Here, we provide the first in-vivo evidence of the role of the Elk1 in cardiogenesis using a zebrafish mutant with disrupted DNA binding domain (elk1-543/-543) and cardiac defects, including valve displacement/elongation and hypertrophic/hyperplastic changes. elk1-543/-543 are predisposed to early embryonic death, with high incidence of heart looping defects and accelerated growth among survivors.RNA-sequencing (RNA-seq) at 6dpf provides insights into the basis of anatomical defects, with upregulation of MAPK components and downregulation of trim63a, encoding a homeostatic protein involved in reducing muscle mass, downregulation of which is associated with Hypertrophic Cardiomyopathy (HCM) in humans.The inverse relationship between MAPK components and Trim63a is well-described although its fundamental basis is unknown. Here we provide the first mechanistic insight into this relationship, indicating that MAPK perturbations likely converge via the TCFs at the trim63a promoter, downregulating trim63a to mediate HCM.RNA-seq at the tail bud stage has allowed us to identify putative, genomically hard-wired compensation mechanisms whereby loss of TCF function causes downregulation of tumor suppressor genes. We hypothesize this promotes proliferation and embryonic survival via non-optimal (compensatory) pathways, and is the fundamental mechanism underlying observed phenotypic defects.The sum of anatomical and molecular changes observed in elk1-543/-543 mimic a group of congenital syndromes known as “RASopathies” in humans. Overall, our data provides high resolution insights into the time line of molecular events underlying RASopathies/MAPK pathway defects and their relationship to molecules imperative in heart patterning and homeostasis.

AB - Elk1 is an ETS Class I, TCF subfamily transcription factor known as a well established downstream effector of the MAPK pathway and implicated in the causation of a variety of cancers. Recent in-vitro evidence places Elk1 and the other TCFs in the context of the cardiogenic transcription factor network but the in-vivo role of the TCFs in cardiogenesis remains unexplored.Here, we provide the first in-vivo evidence of the role of the Elk1 in cardiogenesis using a zebrafish mutant with disrupted DNA binding domain (elk1-543/-543) and cardiac defects, including valve displacement/elongation and hypertrophic/hyperplastic changes. elk1-543/-543 are predisposed to early embryonic death, with high incidence of heart looping defects and accelerated growth among survivors.RNA-sequencing (RNA-seq) at 6dpf provides insights into the basis of anatomical defects, with upregulation of MAPK components and downregulation of trim63a, encoding a homeostatic protein involved in reducing muscle mass, downregulation of which is associated with Hypertrophic Cardiomyopathy (HCM) in humans.The inverse relationship between MAPK components and Trim63a is well-described although its fundamental basis is unknown. Here we provide the first mechanistic insight into this relationship, indicating that MAPK perturbations likely converge via the TCFs at the trim63a promoter, downregulating trim63a to mediate HCM.RNA-seq at the tail bud stage has allowed us to identify putative, genomically hard-wired compensation mechanisms whereby loss of TCF function causes downregulation of tumor suppressor genes. We hypothesize this promotes proliferation and embryonic survival via non-optimal (compensatory) pathways, and is the fundamental mechanism underlying observed phenotypic defects.The sum of anatomical and molecular changes observed in elk1-543/-543 mimic a group of congenital syndromes known as “RASopathies” in humans. Overall, our data provides high resolution insights into the time line of molecular events underlying RASopathies/MAPK pathway defects and their relationship to molecules imperative in heart patterning and homeostasis.

U2 - 10.1016/j.mod.2017.04.027

DO - 10.1016/j.mod.2017.04.027

M3 - Abstract

SP - S30

ER -

Hallab J, Bouveret R, del Monte Nieto G, Hesselson D, Miles LB, Dworkin S et al. Elk1 in congenital and late onset heart disease: at the heart of the matter. 2017. Abstract from 18th International Congress of Developmental Biology, Singapore, Singapore. https://doi.org/10.1016/j.mod.2017.04.027