Notch controls multiple pancreatic cell fate regulators through direct hes1-mediated repression.

Kristian H. de Lichtenberg; Philip A. Seymour; Mette C. Joergensen; Yung-Hae Kim; Anne Grapin-Botton; Mark A. Magnuson; Nikolina Nakic; Jorge Ferrer; Palle. Serup

doi:10.1101/336305

Notch controls multiple pancreatic cell fate regulators through direct hes1-mediated repression.

Kristian H. de Lichtenberg, Philip A. Seymour, Mette C. Joergensen, Yung-Hae Kim, Anne Grapin-Botton, Mark A. Magnuson, Nikolina Nakic, Jorge Ferrer, Palle. Serup

Abstract

Notch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunopptn. with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq anal. of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks assocd. with 354 genes. Among these were genes important for tip/trunk segregation such as Ptf1a and Nkx6-1, genes involved in endocrine differentiation such as Insm1 and Dll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such as Neurog2 and Ascl1. Surprisingly, we find that Hes1 binds a large no. of loci previously reported to bind Ptf1a, including a site downstream of the Nkx6-1 gene. Notably, we find a no. of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently of Neurog3 function, including the tip progenitor/acinar genes; Ptf1a,Gata4, Bhlha15, and Gfi1. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new mol. targets of Notch signaling that may be important for controlling cell fate choices in pancreas development. [on SciFinder(R)]

Original language	English
Journal	bioRxiv, Developmental Biology
Pages (from-to)	1-30
Number of pages	30
DOIs	https://doi.org/10.1101/336305
Publication status	E-pub ahead of print - 2018

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@article{6917b3f001254c18b054bbdea67d9902,

title = "Notch controls multiple pancreatic cell fate regulators through direct hes1-mediated repression.",

abstract = "Notch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunopptn. with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq anal. of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks assocd. with 354 genes. Among these were genes important for tip/trunk segregation such as Ptf1a and Nkx6-1, genes involved in endocrine differentiation such as Insm1 and Dll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such as Neurog2 and Ascl1. Surprisingly, we find that Hes1 binds a large no. of loci previously reported to bind Ptf1a, including a site downstream of the Nkx6-1 gene. Notably, we find a no. of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently of Neurog3 function, including the tip progenitor/acinar genes; Ptf1a,Gata4, Bhlha15, and Gfi1. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new mol. targets of Notch signaling that may be important for controlling cell fate choices in pancreas development. [on SciFinder(R)]",

author = "{de Lichtenberg}, {Kristian H.} and Seymour, {Philip A.} and Joergensen, {Mette C.} and Yung-Hae Kim and Anne Grapin-Botton and Magnuson, {Mark A.} and Nikolina Nakic and Jorge Ferrer and Palle. Serup",

year = "2018",

doi = "10.1101/336305",

language = "English",

pages = "1--30",

journal = "bioRxiv, Developmental Biology",

publisher = "Cold Spring Harbor Laboratory Press",

}

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T1 - Notch controls multiple pancreatic cell fate regulators through direct hes1-mediated repression.

AU - de Lichtenberg, Kristian H.

AU - Seymour, Philip A.

AU - Joergensen, Mette C.

AU - Kim, Yung-Hae

AU - Grapin-Botton, Anne

AU - Magnuson, Mark A.

AU - Nakic, Nikolina

AU - Ferrer, Jorge

AU - Serup, Palle.

PY - 2018

Y1 - 2018

N2 - Notch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunopptn. with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq anal. of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks assocd. with 354 genes. Among these were genes important for tip/trunk segregation such as Ptf1a and Nkx6-1, genes involved in endocrine differentiation such as Insm1 and Dll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such as Neurog2 and Ascl1. Surprisingly, we find that Hes1 binds a large no. of loci previously reported to bind Ptf1a, including a site downstream of the Nkx6-1 gene. Notably, we find a no. of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently of Neurog3 function, including the tip progenitor/acinar genes; Ptf1a,Gata4, Bhlha15, and Gfi1. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new mol. targets of Notch signaling that may be important for controlling cell fate choices in pancreas development. [on SciFinder(R)]

AB - Notch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunopptn. with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq anal. of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks assocd. with 354 genes. Among these were genes important for tip/trunk segregation such as Ptf1a and Nkx6-1, genes involved in endocrine differentiation such as Insm1 and Dll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such as Neurog2 and Ascl1. Surprisingly, we find that Hes1 binds a large no. of loci previously reported to bind Ptf1a, including a site downstream of the Nkx6-1 gene. Notably, we find a no. of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently of Neurog3 function, including the tip progenitor/acinar genes; Ptf1a,Gata4, Bhlha15, and Gfi1. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new mol. targets of Notch signaling that may be important for controlling cell fate choices in pancreas development. [on SciFinder(R)]

U2 - 10.1101/336305

DO - 10.1101/336305

M3 - Journal article

SP - 1

EP - 30

JO - bioRxiv, Developmental Biology

JF - bioRxiv, Developmental Biology

ER -

Notch controls multiple pancreatic cell fate regulators through direct hes1-mediated repression.

Abstract

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