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Epigenetic regulation during fetal femur development: DNA methylation matters

Epigenetic regulation during fetal femur development: DNA methylation matters
Epigenetic regulation during fetal femur development: DNA methylation matters
Epigenetic modifications are heritable changes in gene expression without changes in DNA sequence. DNA methylation has been implicated in the control of several cellular processes including differentiation, gene regulation, development, genomic imprinting and X-chromosome inactivation. Methylated cytosine residues at CpG dinucleotides are commonly associated with gene repression; conversely, strategic loss of methylation during development could lead to activation of lineage-specific genes. Evidence is emerging that bone development and growth are programmed; although, interestingly, bone is constantly remodelled throughout life. Using human embryonic stem cells, human fetal bone cells (HFBCs), adult chondrocytes and STRO-1+ marrow stromal cells from human bone marrow, we have examined a spectrum of developmental stages of femur development and the role of DNA methylation therein. Using pyrosequencing methodology we analysed the status of methylation of genes implicated in bone biology; furthermore, we correlated these methylation levels with gene expression levels using qRT-PCR and protein distribution during fetal development evaluated using immunohistochemistry. We found that during fetal femur development DNA methylation inversely correlates with expression of genes including iNOS (NOS2) and COL9A1, but not catabolic genes including MMP13 and IL1B. Furthermore, significant demethylation was evident in the osteocalcin promoter between the fetal and adult developmental stages. Increased TET1 expression and decreased expression of DNA (cytosine-5-)-methyltransferase 1 (DNMT1) in adult chondrocytes compared to HFBCs could contribute to the loss of methylation observed during fetal development. HFBC multipotency confirms these cells to be an ideal developmental system for investigation of DNA methylation regulation. In conclusion, these findings demonstrate the role of epigenetic regulation, specifically DNA methylation, in bone development, informing and opening new possibilities in development of strategies for bone repair/tissue engineering.

1932-6203
e54957
Neves, Nuno M.
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de Andrés, María C.
9b3834e7-972f-410d-a8cb-199abd035b87
Kingham, Emmajayne
4ad3641f-bdca-464a-b5e8-cb1fc995409a
Imagawa, Kei
cfdeef65-8259-4f0c-943a-0d439aab3193
Gonzalez, Antonio
41d6e3cb-9a9a-499a-89b3-a2872864e9d3
Roach, Helmtrud I.
ca2ff1f4-1ada-4c56-9097-cd27ca4d199e
Wilson, David I.
1500fca1-7082-4271-95f4-691f1d1252a2
Oreffo, Richard O. C.
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Neves, Nuno M.
3ab9ccfd-52c1-42ad-8595-19492562f284
de Andrés, María C.
9b3834e7-972f-410d-a8cb-199abd035b87
Kingham, Emmajayne
4ad3641f-bdca-464a-b5e8-cb1fc995409a
Imagawa, Kei
cfdeef65-8259-4f0c-943a-0d439aab3193
Gonzalez, Antonio
41d6e3cb-9a9a-499a-89b3-a2872864e9d3
Roach, Helmtrud I.
ca2ff1f4-1ada-4c56-9097-cd27ca4d199e
Wilson, David I.
1500fca1-7082-4271-95f4-691f1d1252a2
Oreffo, Richard O. C.
ff9fff72-6855-4d0f-bfb2-311d0e8f3778

Neves, Nuno M., de Andrés, María C., Kingham, Emmajayne, Imagawa, Kei, Gonzalez, Antonio, Roach, Helmtrud I., Wilson, David I. and Oreffo, Richard O. C. (2013) Epigenetic regulation during fetal femur development: DNA methylation matters. PLoS ONE, 8 (1), e54957. (doi:10.1371/journal.pone.0054957).

Record type: Article

Abstract

Epigenetic modifications are heritable changes in gene expression without changes in DNA sequence. DNA methylation has been implicated in the control of several cellular processes including differentiation, gene regulation, development, genomic imprinting and X-chromosome inactivation. Methylated cytosine residues at CpG dinucleotides are commonly associated with gene repression; conversely, strategic loss of methylation during development could lead to activation of lineage-specific genes. Evidence is emerging that bone development and growth are programmed; although, interestingly, bone is constantly remodelled throughout life. Using human embryonic stem cells, human fetal bone cells (HFBCs), adult chondrocytes and STRO-1+ marrow stromal cells from human bone marrow, we have examined a spectrum of developmental stages of femur development and the role of DNA methylation therein. Using pyrosequencing methodology we analysed the status of methylation of genes implicated in bone biology; furthermore, we correlated these methylation levels with gene expression levels using qRT-PCR and protein distribution during fetal development evaluated using immunohistochemistry. We found that during fetal femur development DNA methylation inversely correlates with expression of genes including iNOS (NOS2) and COL9A1, but not catabolic genes including MMP13 and IL1B. Furthermore, significant demethylation was evident in the osteocalcin promoter between the fetal and adult developmental stages. Increased TET1 expression and decreased expression of DNA (cytosine-5-)-methyltransferase 1 (DNMT1) in adult chondrocytes compared to HFBCs could contribute to the loss of methylation observed during fetal development. HFBC multipotency confirms these cells to be an ideal developmental system for investigation of DNA methylation regulation. In conclusion, these findings demonstrate the role of epigenetic regulation, specifically DNA methylation, in bone development, informing and opening new possibilities in development of strategies for bone repair/tissue engineering.

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Published date: 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 348162
URI: http://eprints.soton.ac.uk/id/eprint/348162
ISSN: 1932-6203
PURE UUID: b4e4eb83-3db1-42b9-950f-8dde91825ebc
ORCID for Richard O. C. Oreffo: ORCID iD orcid.org/0000-0001-5995-6726

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Date deposited: 07 Feb 2013 14:00
Last modified: 28 Oct 2023 01:46

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Contributors

Author: Nuno M. Neves
Author: María C. de Andrés
Author: Emmajayne Kingham
Author: Kei Imagawa
Author: Antonio Gonzalez
Author: Helmtrud I. Roach
Author: David I. Wilson

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