The parathyroid hormone-regulated transcriptome in osteocytes: Parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function

Hillary C. St. John, Mark B. Meyer, Nancy A. Benkusky, Alex H. Carlson, Mathew Prideaux, Lynda Bonewald, J. Wesley Pike

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examined the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH's effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte-specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA-activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA-mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone-regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage.

Original languageEnglish (US)
Pages (from-to)81-91
Number of pages11
JournalBone
Volume72
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Fingerprint

Osteocytes
Calcitriol
Parathyroid Hormone
Transcriptome
Gene Expression
Genes
Hormones
Osteoblasts
Histones
Bone Matrix
Epigenomics
Transcription Factors
Binding Sites

Keywords

  • ChIP-seq
  • Osteocyte
  • PTH
  • RNA-seq
  • Transcriptional regulation

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

The parathyroid hormone-regulated transcriptome in osteocytes : Parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function. / St. John, Hillary C.; Meyer, Mark B.; Benkusky, Nancy A.; Carlson, Alex H.; Prideaux, Mathew; Bonewald, Lynda; Wesley Pike, J.

In: Bone, Vol. 72, 01.03.2015, p. 81-91.

Research output: Contribution to journalArticle

St. John, Hillary C. ; Meyer, Mark B. ; Benkusky, Nancy A. ; Carlson, Alex H. ; Prideaux, Mathew ; Bonewald, Lynda ; Wesley Pike, J. / The parathyroid hormone-regulated transcriptome in osteocytes : Parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function. In: Bone. 2015 ; Vol. 72. pp. 81-91.
@article{68085abf464443cc8e63a8659eef7982,
title = "The parathyroid hormone-regulated transcriptome in osteocytes: Parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function",
abstract = "Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examined the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH's effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte-specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA-activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA-mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone-regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage.",
keywords = "ChIP-seq, Osteocyte, PTH, RNA-seq, Transcriptional regulation",
author = "{St. John}, {Hillary C.} and Meyer, {Mark B.} and Benkusky, {Nancy A.} and Carlson, {Alex H.} and Mathew Prideaux and Lynda Bonewald and {Wesley Pike}, J.",
year = "2015",
month = "3",
day = "1",
doi = "10.1016/j.bone.2014.11.010",
language = "English (US)",
volume = "72",
pages = "81--91",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - The parathyroid hormone-regulated transcriptome in osteocytes

T2 - Parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function

AU - St. John, Hillary C.

AU - Meyer, Mark B.

AU - Benkusky, Nancy A.

AU - Carlson, Alex H.

AU - Prideaux, Mathew

AU - Bonewald, Lynda

AU - Wesley Pike, J.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examined the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH's effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte-specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA-activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA-mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone-regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage.

AB - Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examined the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH's effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte-specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA-activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA-mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone-regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage.

KW - ChIP-seq

KW - Osteocyte

KW - PTH

KW - RNA-seq

KW - Transcriptional regulation

UR - http://www.scopus.com/inward/record.url?scp=84918819638&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84918819638&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2014.11.010

DO - 10.1016/j.bone.2014.11.010

M3 - Article

C2 - 25460572

AN - SCOPUS:84918819638

VL - 72

SP - 81

EP - 91

JO - Bone

JF - Bone

SN - 8756-3282

ER -