Developmental origins of disease and determinants of chromatin structure: Maternal diet modifies the primate fetal epigenome

Kjersti M. Aagaard-Tillery, Kevin Grove, Jacalyn Bishop, Xingrao Ke, Qi Fu, Robert McKnight, Robert H. Lane

    Research output: Contribution to journalArticle

    264 Citations (Scopus)

    Abstract

    Chromatin structure is epigenetically altered via covalent modifications of histones to allow for heritable gene regulation without altering the nucleotide sequence. Multiple lines of evidence from rodents have established a role for epigenetic remodeling in regulating gene transcription in response to an altered gestational milieu. However, to date, it is unknown whether variations in the intrauterine environment in primates similarly induce changes in key determinants of hepatic chromatin structure. We hypothesized that a maternal high-fat diet would alter the epigenomic profile of the developing offspring, which would result in alterations in fetal gene expression. Age- and weight-matched adult female Japanese macaques were placed on control (13% fat) or high-fat (35% fat) breeder diets and mated annually over a 4-year interval. Fetuses in successive years were delivered near term (e130 of 167 days) and underwent necropsy with tissue harvest. Fetal histones were acid extracted for characterization of H3 modification and chromatin immunoprecipitation (ChIP) with differential display PCR; fetal RNA, DNA, and cytoplasmic and nuclear protein extracts were similarly extracted for comparison. Chronic consumption of a maternal high-fat diet results in a threefold increase in fetal liver triglycerides and histologic correlates of non-alcoholic fatty liver disease. These gross changes in the fetal liver are accompanied by a statistically significant hyperacetylation of fetal hepatic tissue at H3K14 (199.85±9.64 vs 88.8±45.4; P=0.038) with a trend towards the increased acetylation at H3K9 (140.9±38.7 vs 46.6±6.53; P=0.097) and at H3K18 (69.0±3.54 vs 58.0±4.04; P=0.096). However, epigenetic modifications on fetal hepatic H3 associated with gene repression were absent or subtle (P>0.05). Subsequent characterization of key epigenetic determinants associated with H3 acetylation marks revealed similar significant alterations in association with a high-fat maternal diet (e.g., relative fetal histone deacetylase 1 (HDAC1) gene expression 0.61±0.25; P=0.011). Consistent with our mRNA expression profile, fetal nuclear extracts from offspring of high-fat diet animals were observed to be significantly relatively deplete of HDAC1 protein (36.07±6.73 vs 83.18±7.51; P= 0.006) and in vitro HDAC functional activity (0.252±0.03 vs 0.698±0.02; P

    Original languageEnglish (US)
    Pages (from-to)91-102
    Number of pages12
    JournalJournal of Molecular Endocrinology
    Volume41
    Issue number1-2
    DOIs
    StatePublished - Jul 2008

    Fingerprint

    Primates
    Chromatin
    High Fat Diet
    Epigenomics
    Mothers
    Diet
    Histone Deacetylase 1
    Liver
    Fats
    Acetylation
    Fetus
    Histone Code
    Genes
    Gene Expression
    Chromatin Immunoprecipitation
    Macaca
    Nuclear Proteins
    Histones
    Rodentia
    Triglycerides

    ASJC Scopus subject areas

    • Endocrinology

    Cite this

    Developmental origins of disease and determinants of chromatin structure : Maternal diet modifies the primate fetal epigenome. / Aagaard-Tillery, Kjersti M.; Grove, Kevin; Bishop, Jacalyn; Ke, Xingrao; Fu, Qi; McKnight, Robert; Lane, Robert H.

    In: Journal of Molecular Endocrinology, Vol. 41, No. 1-2, 07.2008, p. 91-102.

    Research output: Contribution to journalArticle

    Aagaard-Tillery, Kjersti M. ; Grove, Kevin ; Bishop, Jacalyn ; Ke, Xingrao ; Fu, Qi ; McKnight, Robert ; Lane, Robert H. / Developmental origins of disease and determinants of chromatin structure : Maternal diet modifies the primate fetal epigenome. In: Journal of Molecular Endocrinology. 2008 ; Vol. 41, No. 1-2. pp. 91-102.
    @article{f2a13a8c31564aa389770eaab9980c7d,
    title = "Developmental origins of disease and determinants of chromatin structure: Maternal diet modifies the primate fetal epigenome",
    abstract = "Chromatin structure is epigenetically altered via covalent modifications of histones to allow for heritable gene regulation without altering the nucleotide sequence. Multiple lines of evidence from rodents have established a role for epigenetic remodeling in regulating gene transcription in response to an altered gestational milieu. However, to date, it is unknown whether variations in the intrauterine environment in primates similarly induce changes in key determinants of hepatic chromatin structure. We hypothesized that a maternal high-fat diet would alter the epigenomic profile of the developing offspring, which would result in alterations in fetal gene expression. Age- and weight-matched adult female Japanese macaques were placed on control (13{\%} fat) or high-fat (35{\%} fat) breeder diets and mated annually over a 4-year interval. Fetuses in successive years were delivered near term (e130 of 167 days) and underwent necropsy with tissue harvest. Fetal histones were acid extracted for characterization of H3 modification and chromatin immunoprecipitation (ChIP) with differential display PCR; fetal RNA, DNA, and cytoplasmic and nuclear protein extracts were similarly extracted for comparison. Chronic consumption of a maternal high-fat diet results in a threefold increase in fetal liver triglycerides and histologic correlates of non-alcoholic fatty liver disease. These gross changes in the fetal liver are accompanied by a statistically significant hyperacetylation of fetal hepatic tissue at H3K14 (199.85±9.64 vs 88.8±45.4; P=0.038) with a trend towards the increased acetylation at H3K9 (140.9±38.7 vs 46.6±6.53; P=0.097) and at H3K18 (69.0±3.54 vs 58.0±4.04; P=0.096). However, epigenetic modifications on fetal hepatic H3 associated with gene repression were absent or subtle (P>0.05). Subsequent characterization of key epigenetic determinants associated with H3 acetylation marks revealed similar significant alterations in association with a high-fat maternal diet (e.g., relative fetal histone deacetylase 1 (HDAC1) gene expression 0.61±0.25; P=0.011). Consistent with our mRNA expression profile, fetal nuclear extracts from offspring of high-fat diet animals were observed to be significantly relatively deplete of HDAC1 protein (36.07±6.73 vs 83.18±7.51; P= 0.006) and in vitro HDAC functional activity (0.252±0.03 vs 0.698±0.02; P",
    author = "Aagaard-Tillery, {Kjersti M.} and Kevin Grove and Jacalyn Bishop and Xingrao Ke and Qi Fu and Robert McKnight and Lane, {Robert H.}",
    year = "2008",
    month = "7",
    doi = "10.1677/JME-08-0025",
    language = "English (US)",
    volume = "41",
    pages = "91--102",
    journal = "Journal of Molecular Endocrinology",
    issn = "0952-5041",
    publisher = "Society for Endocrinology",
    number = "1-2",

    }

    TY - JOUR

    T1 - Developmental origins of disease and determinants of chromatin structure

    T2 - Maternal diet modifies the primate fetal epigenome

    AU - Aagaard-Tillery, Kjersti M.

    AU - Grove, Kevin

    AU - Bishop, Jacalyn

    AU - Ke, Xingrao

    AU - Fu, Qi

    AU - McKnight, Robert

    AU - Lane, Robert H.

    PY - 2008/7

    Y1 - 2008/7

    N2 - Chromatin structure is epigenetically altered via covalent modifications of histones to allow for heritable gene regulation without altering the nucleotide sequence. Multiple lines of evidence from rodents have established a role for epigenetic remodeling in regulating gene transcription in response to an altered gestational milieu. However, to date, it is unknown whether variations in the intrauterine environment in primates similarly induce changes in key determinants of hepatic chromatin structure. We hypothesized that a maternal high-fat diet would alter the epigenomic profile of the developing offspring, which would result in alterations in fetal gene expression. Age- and weight-matched adult female Japanese macaques were placed on control (13% fat) or high-fat (35% fat) breeder diets and mated annually over a 4-year interval. Fetuses in successive years were delivered near term (e130 of 167 days) and underwent necropsy with tissue harvest. Fetal histones were acid extracted for characterization of H3 modification and chromatin immunoprecipitation (ChIP) with differential display PCR; fetal RNA, DNA, and cytoplasmic and nuclear protein extracts were similarly extracted for comparison. Chronic consumption of a maternal high-fat diet results in a threefold increase in fetal liver triglycerides and histologic correlates of non-alcoholic fatty liver disease. These gross changes in the fetal liver are accompanied by a statistically significant hyperacetylation of fetal hepatic tissue at H3K14 (199.85±9.64 vs 88.8±45.4; P=0.038) with a trend towards the increased acetylation at H3K9 (140.9±38.7 vs 46.6±6.53; P=0.097) and at H3K18 (69.0±3.54 vs 58.0±4.04; P=0.096). However, epigenetic modifications on fetal hepatic H3 associated with gene repression were absent or subtle (P>0.05). Subsequent characterization of key epigenetic determinants associated with H3 acetylation marks revealed similar significant alterations in association with a high-fat maternal diet (e.g., relative fetal histone deacetylase 1 (HDAC1) gene expression 0.61±0.25; P=0.011). Consistent with our mRNA expression profile, fetal nuclear extracts from offspring of high-fat diet animals were observed to be significantly relatively deplete of HDAC1 protein (36.07±6.73 vs 83.18±7.51; P= 0.006) and in vitro HDAC functional activity (0.252±0.03 vs 0.698±0.02; P

    AB - Chromatin structure is epigenetically altered via covalent modifications of histones to allow for heritable gene regulation without altering the nucleotide sequence. Multiple lines of evidence from rodents have established a role for epigenetic remodeling in regulating gene transcription in response to an altered gestational milieu. However, to date, it is unknown whether variations in the intrauterine environment in primates similarly induce changes in key determinants of hepatic chromatin structure. We hypothesized that a maternal high-fat diet would alter the epigenomic profile of the developing offspring, which would result in alterations in fetal gene expression. Age- and weight-matched adult female Japanese macaques were placed on control (13% fat) or high-fat (35% fat) breeder diets and mated annually over a 4-year interval. Fetuses in successive years were delivered near term (e130 of 167 days) and underwent necropsy with tissue harvest. Fetal histones were acid extracted for characterization of H3 modification and chromatin immunoprecipitation (ChIP) with differential display PCR; fetal RNA, DNA, and cytoplasmic and nuclear protein extracts were similarly extracted for comparison. Chronic consumption of a maternal high-fat diet results in a threefold increase in fetal liver triglycerides and histologic correlates of non-alcoholic fatty liver disease. These gross changes in the fetal liver are accompanied by a statistically significant hyperacetylation of fetal hepatic tissue at H3K14 (199.85±9.64 vs 88.8±45.4; P=0.038) with a trend towards the increased acetylation at H3K9 (140.9±38.7 vs 46.6±6.53; P=0.097) and at H3K18 (69.0±3.54 vs 58.0±4.04; P=0.096). However, epigenetic modifications on fetal hepatic H3 associated with gene repression were absent or subtle (P>0.05). Subsequent characterization of key epigenetic determinants associated with H3 acetylation marks revealed similar significant alterations in association with a high-fat maternal diet (e.g., relative fetal histone deacetylase 1 (HDAC1) gene expression 0.61±0.25; P=0.011). Consistent with our mRNA expression profile, fetal nuclear extracts from offspring of high-fat diet animals were observed to be significantly relatively deplete of HDAC1 protein (36.07±6.73 vs 83.18±7.51; P= 0.006) and in vitro HDAC functional activity (0.252±0.03 vs 0.698±0.02; P

    UR - http://www.scopus.com/inward/record.url?scp=51349085004&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=51349085004&partnerID=8YFLogxK

    U2 - 10.1677/JME-08-0025

    DO - 10.1677/JME-08-0025

    M3 - Article

    C2 - 18515302

    AN - SCOPUS:51349085004

    VL - 41

    SP - 91

    EP - 102

    JO - Journal of Molecular Endocrinology

    JF - Journal of Molecular Endocrinology

    SN - 0952-5041

    IS - 1-2

    ER -