Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1

Cong Guo, Anton E. Ludvik, Michelle E. Arlotto, M. Geoffrey Hayes, Loren L. Armstrong, Denise M. Scholtens, Christopher D. Brown, Christopher B. Newgard, Thomas C. Becker, Brian T. Layden, William L. Lowe, Timothy E. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Maternal glucose levels during pregnancy impact the developing fetus, affecting metabolic health both early and later on in life. Both genetic and environmental factors influence maternal metabolism, but little is known about the genetic mechanisms that alter glucose metabolism during pregnancy. Here, we report that haplotypes previously associated with gestational hyperglycaemia in the third trimester disrupt regulatory element activity and reduce expression of the nearby HKDC1 gene. We further find that experimentally reducing or increasing HKDC1 expression reduces or increases hexokinase activity, respectively, in multiple cellular models; in addition, purified HKDC1 protein has hexokinase activity in vitro. Together, these results suggest a novel mechanism of gestational glucose regulation in which the effects of genetic variants in multiple regulatory elements alter glucose homeostasis by coordinately reducing expression of the novel hexokinase HKDC1.

Original languageEnglish (US)
Article number6069
JournalNature communications
Volume6
DOIs
StatePublished - Feb 4 2015

Fingerprint

hexokinase
hyperglycemia
Hexokinase
glucose
Hyperglycemia
Glucose
pregnancy
metabolism
Metabolism
Mothers
homeostasis
Pregnancy
fetuses
Third Pregnancy Trimester
genes
Haplotypes
health
Fetus
Homeostasis
Genes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Guo, Cong ; Ludvik, Anton E. ; Arlotto, Michelle E. ; Hayes, M. Geoffrey ; Armstrong, Loren L. ; Scholtens, Denise M. ; Brown, Christopher D. ; Newgard, Christopher B. ; Becker, Thomas C. ; Layden, Brian T. ; Lowe, William L. ; Reddy, Timothy E. / Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. In: Nature communications. 2015 ; Vol. 6.
@article{8a45f2d274b547968b35905e5140ade3,
title = "Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1",
abstract = "Maternal glucose levels during pregnancy impact the developing fetus, affecting metabolic health both early and later on in life. Both genetic and environmental factors influence maternal metabolism, but little is known about the genetic mechanisms that alter glucose metabolism during pregnancy. Here, we report that haplotypes previously associated with gestational hyperglycaemia in the third trimester disrupt regulatory element activity and reduce expression of the nearby HKDC1 gene. We further find that experimentally reducing or increasing HKDC1 expression reduces or increases hexokinase activity, respectively, in multiple cellular models; in addition, purified HKDC1 protein has hexokinase activity in vitro. Together, these results suggest a novel mechanism of gestational glucose regulation in which the effects of genetic variants in multiple regulatory elements alter glucose homeostasis by coordinately reducing expression of the novel hexokinase HKDC1.",
author = "Cong Guo and Ludvik, {Anton E.} and Arlotto, {Michelle E.} and Hayes, {M. Geoffrey} and Armstrong, {Loren L.} and Scholtens, {Denise M.} and Brown, {Christopher D.} and Newgard, {Christopher B.} and Becker, {Thomas C.} and Layden, {Brian T.} and Lowe, {William L.} and Reddy, {Timothy E.}",
year = "2015",
month = "2",
day = "4",
doi = "10.1038/ncomms7069",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. / Guo, Cong; Ludvik, Anton E.; Arlotto, Michelle E.; Hayes, M. Geoffrey; Armstrong, Loren L.; Scholtens, Denise M.; Brown, Christopher D.; Newgard, Christopher B.; Becker, Thomas C.; Layden, Brian T.; Lowe, William L.; Reddy, Timothy E.

In: Nature communications, Vol. 6, 6069, 04.02.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1

AU - Guo, Cong

AU - Ludvik, Anton E.

AU - Arlotto, Michelle E.

AU - Hayes, M. Geoffrey

AU - Armstrong, Loren L.

AU - Scholtens, Denise M.

AU - Brown, Christopher D.

AU - Newgard, Christopher B.

AU - Becker, Thomas C.

AU - Layden, Brian T.

AU - Lowe, William L.

AU - Reddy, Timothy E.

PY - 2015/2/4

Y1 - 2015/2/4

N2 - Maternal glucose levels during pregnancy impact the developing fetus, affecting metabolic health both early and later on in life. Both genetic and environmental factors influence maternal metabolism, but little is known about the genetic mechanisms that alter glucose metabolism during pregnancy. Here, we report that haplotypes previously associated with gestational hyperglycaemia in the third trimester disrupt regulatory element activity and reduce expression of the nearby HKDC1 gene. We further find that experimentally reducing or increasing HKDC1 expression reduces or increases hexokinase activity, respectively, in multiple cellular models; in addition, purified HKDC1 protein has hexokinase activity in vitro. Together, these results suggest a novel mechanism of gestational glucose regulation in which the effects of genetic variants in multiple regulatory elements alter glucose homeostasis by coordinately reducing expression of the novel hexokinase HKDC1.

AB - Maternal glucose levels during pregnancy impact the developing fetus, affecting metabolic health both early and later on in life. Both genetic and environmental factors influence maternal metabolism, but little is known about the genetic mechanisms that alter glucose metabolism during pregnancy. Here, we report that haplotypes previously associated with gestational hyperglycaemia in the third trimester disrupt regulatory element activity and reduce expression of the nearby HKDC1 gene. We further find that experimentally reducing or increasing HKDC1 expression reduces or increases hexokinase activity, respectively, in multiple cellular models; in addition, purified HKDC1 protein has hexokinase activity in vitro. Together, these results suggest a novel mechanism of gestational glucose regulation in which the effects of genetic variants in multiple regulatory elements alter glucose homeostasis by coordinately reducing expression of the novel hexokinase HKDC1.

UR - http://www.scopus.com/inward/record.url?scp=84938835765&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938835765&partnerID=8YFLogxK

U2 - 10.1038/ncomms7069

DO - 10.1038/ncomms7069

M3 - Article

C2 - 25648650

AN - SCOPUS:84938835765

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6069

ER -