Transcription factors GATA4 and GATA6 in pediatric liver disease

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

GATA transcription factors are required for the normal differentiation of various tissues, including liver, but their expression is low in normal postnatal hepatocytes. Aberrant expression of GATA factors has been connected to several human diseases. Hepatoblastoma (HB) is a rare liver malignancy of small children, with a largely unknown molecular pathology, histologically resembling fetal liver tissue. Biliary atresia (BA) is a neonatal cholestatic condition caused by fibroinflammatory obstruction of the extrahepatic bile ducts, with subsequent histological changes in liver. This thesis work demonstrates that GATA4 is frequently overexpressed in childhood HBs. The effects of GATA4 in HB cell malignancy were studied in vitro utilizing a human HB cell line. The changes in cell function and gene expression caused by modification of GATA4 levels were analyzed. We found that GATA4 1) protects HB cells from the commonly used cytostatic drug doxorubicin by regulating the intrinsic apoptotic pathway, and 2) shifts the transcriptomic profile of HB cells to more mesenchymal-type and enhances their migration. A second focus of this thesis is the role of GATA6 transcription factor in BA pathogenesis. We found that GATA6, normally restricted to biliary epithelium in postnatal liver, is highly expressed in the hepatocytes undergoing ductal metaplasia in livers of BA patients. GATA6 expression correlates to known prognostic markers, including bile ductule expansion and age at portoenterostomy. The expression of GATA6 decreases significantly after resolution of cholestasis by successful portoenterostomy. Analogously to its increased expression in BA, GATA6 is also upregulated in the hepatocytes of two mouse models with biliary obstruction. Furthermore, forced expression of GATA6 in two human hepatocyte cell models drives their gene expression towards cholangiocyte lineage. Taken together, transcription factors GATA4 and GATA6 are essential for the initial differentiation of hepatoblasts and for liver organogenesis. Compared to normal postnatal liver, their expression is upregulated in these two pediatric diseases of the liver. GATA4 and GATA6 are here demonstrated as putative drivers of hepatocyte neoplasia and metaplasia.
Original languageEnglish
Supervisors/Advisors
  • Heikinheimo, Markku, Supervisor
Award date7 Sep 2018
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4136-1
Electronic ISBNs978-951-51-4137-8
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • GATA6 Transcription Factor
  • GATA4 Transcription Factor
  • Hepatoblastoma
  • +etiology
  • Biliary Atresia
  • Hepatocytes
  • Cell Line
  • Cholestasis
  • Doxorubicin
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Carcinoma, Hepatocellular
  • Epithelial-Mesenchymal Transition
  • 3122 Cancers
  • 3123 Gynaecology and paediatrics

Cite this

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title = "Transcription factors GATA4 and GATA6 in pediatric liver disease",
abstract = "GATA transcription factors are required for the normal differentiation of various tissues, including liver, but their expression is low in normal postnatal hepatocytes. Aberrant expression of GATA factors has been connected to several human diseases. Hepatoblastoma (HB) is a rare liver malignancy of small children, with a largely unknown molecular pathology, histologically resembling fetal liver tissue. Biliary atresia (BA) is a neonatal cholestatic condition caused by fibroinflammatory obstruction of the extrahepatic bile ducts, with subsequent histological changes in liver. This thesis work demonstrates that GATA4 is frequently overexpressed in childhood HBs. The effects of GATA4 in HB cell malignancy were studied in vitro utilizing a human HB cell line. The changes in cell function and gene expression caused by modification of GATA4 levels were analyzed. We found that GATA4 1) protects HB cells from the commonly used cytostatic drug doxorubicin by regulating the intrinsic apoptotic pathway, and 2) shifts the transcriptomic profile of HB cells to more mesenchymal-type and enhances their migration. A second focus of this thesis is the role of GATA6 transcription factor in BA pathogenesis. We found that GATA6, normally restricted to biliary epithelium in postnatal liver, is highly expressed in the hepatocytes undergoing ductal metaplasia in livers of BA patients. GATA6 expression correlates to known prognostic markers, including bile ductule expansion and age at portoenterostomy. The expression of GATA6 decreases significantly after resolution of cholestasis by successful portoenterostomy. Analogously to its increased expression in BA, GATA6 is also upregulated in the hepatocytes of two mouse models with biliary obstruction. Furthermore, forced expression of GATA6 in two human hepatocyte cell models drives their gene expression towards cholangiocyte lineage. Taken together, transcription factors GATA4 and GATA6 are essential for the initial differentiation of hepatoblasts and for liver organogenesis. Compared to normal postnatal liver, their expression is upregulated in these two pediatric diseases of the liver. GATA4 and GATA6 are here demonstrated as putative drivers of hepatocyte neoplasia and metaplasia.",
keywords = "GATA6 Transcription Factor, GATA4 Transcription Factor, Hepatoblastoma, +etiology, Biliary Atresia, Hepatocytes, Cell Line, Cholestasis, Doxorubicin, Gene Expression Regulation, Neoplastic, Gene Silencing, Carcinoma, Hepatocellular, Epithelial-Mesenchymal Transition, 3122 Cancers, 3123 Gynaecology and paediatrics",
author = "Tea Soini",
note = "M1 - 77 s. + liitteet",
year = "2018",
language = "English",
isbn = "978-951-51-4136-1",
publisher = "[T. Soini]",
address = "Finland",

}

Transcription factors GATA4 and GATA6 in pediatric liver disease. / Soini, Tea.

Helsinki : [T. Soini], 2018. 77 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Transcription factors GATA4 and GATA6 in pediatric liver disease

AU - Soini, Tea

N1 - M1 - 77 s. + liitteet

PY - 2018

Y1 - 2018

N2 - GATA transcription factors are required for the normal differentiation of various tissues, including liver, but their expression is low in normal postnatal hepatocytes. Aberrant expression of GATA factors has been connected to several human diseases. Hepatoblastoma (HB) is a rare liver malignancy of small children, with a largely unknown molecular pathology, histologically resembling fetal liver tissue. Biliary atresia (BA) is a neonatal cholestatic condition caused by fibroinflammatory obstruction of the extrahepatic bile ducts, with subsequent histological changes in liver. This thesis work demonstrates that GATA4 is frequently overexpressed in childhood HBs. The effects of GATA4 in HB cell malignancy were studied in vitro utilizing a human HB cell line. The changes in cell function and gene expression caused by modification of GATA4 levels were analyzed. We found that GATA4 1) protects HB cells from the commonly used cytostatic drug doxorubicin by regulating the intrinsic apoptotic pathway, and 2) shifts the transcriptomic profile of HB cells to more mesenchymal-type and enhances their migration. A second focus of this thesis is the role of GATA6 transcription factor in BA pathogenesis. We found that GATA6, normally restricted to biliary epithelium in postnatal liver, is highly expressed in the hepatocytes undergoing ductal metaplasia in livers of BA patients. GATA6 expression correlates to known prognostic markers, including bile ductule expansion and age at portoenterostomy. The expression of GATA6 decreases significantly after resolution of cholestasis by successful portoenterostomy. Analogously to its increased expression in BA, GATA6 is also upregulated in the hepatocytes of two mouse models with biliary obstruction. Furthermore, forced expression of GATA6 in two human hepatocyte cell models drives their gene expression towards cholangiocyte lineage. Taken together, transcription factors GATA4 and GATA6 are essential for the initial differentiation of hepatoblasts and for liver organogenesis. Compared to normal postnatal liver, their expression is upregulated in these two pediatric diseases of the liver. GATA4 and GATA6 are here demonstrated as putative drivers of hepatocyte neoplasia and metaplasia.

AB - GATA transcription factors are required for the normal differentiation of various tissues, including liver, but their expression is low in normal postnatal hepatocytes. Aberrant expression of GATA factors has been connected to several human diseases. Hepatoblastoma (HB) is a rare liver malignancy of small children, with a largely unknown molecular pathology, histologically resembling fetal liver tissue. Biliary atresia (BA) is a neonatal cholestatic condition caused by fibroinflammatory obstruction of the extrahepatic bile ducts, with subsequent histological changes in liver. This thesis work demonstrates that GATA4 is frequently overexpressed in childhood HBs. The effects of GATA4 in HB cell malignancy were studied in vitro utilizing a human HB cell line. The changes in cell function and gene expression caused by modification of GATA4 levels were analyzed. We found that GATA4 1) protects HB cells from the commonly used cytostatic drug doxorubicin by regulating the intrinsic apoptotic pathway, and 2) shifts the transcriptomic profile of HB cells to more mesenchymal-type and enhances their migration. A second focus of this thesis is the role of GATA6 transcription factor in BA pathogenesis. We found that GATA6, normally restricted to biliary epithelium in postnatal liver, is highly expressed in the hepatocytes undergoing ductal metaplasia in livers of BA patients. GATA6 expression correlates to known prognostic markers, including bile ductule expansion and age at portoenterostomy. The expression of GATA6 decreases significantly after resolution of cholestasis by successful portoenterostomy. Analogously to its increased expression in BA, GATA6 is also upregulated in the hepatocytes of two mouse models with biliary obstruction. Furthermore, forced expression of GATA6 in two human hepatocyte cell models drives their gene expression towards cholangiocyte lineage. Taken together, transcription factors GATA4 and GATA6 are essential for the initial differentiation of hepatoblasts and for liver organogenesis. Compared to normal postnatal liver, their expression is upregulated in these two pediatric diseases of the liver. GATA4 and GATA6 are here demonstrated as putative drivers of hepatocyte neoplasia and metaplasia.

KW - GATA6 Transcription Factor

KW - GATA4 Transcription Factor

KW - Hepatoblastoma

KW - +etiology

KW - Biliary Atresia

KW - Hepatocytes

KW - Cell Line

KW - Cholestasis

KW - Doxorubicin

KW - Gene Expression Regulation, Neoplastic

KW - Gene Silencing

KW - Carcinoma, Hepatocellular

KW - Epithelial-Mesenchymal Transition

KW - 3122 Cancers

KW - 3123 Gynaecology and paediatrics

M3 - Doctoral Thesis

SN - 978-951-51-4136-1

PB - [T. Soini]

CY - Helsinki

ER -