An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden

Sumiko Kurachi, Jeffrey S. Huo, Afshin Ameri, Kezhong Zhang, Akiyasu C. Yoshizawa, Kotoku Kurachi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Regulation of age-related changes in gene expression underlies many diseases. We previously discovered the first puberty-onset gene switch, the age-related stability element (ASE)/age-related increase element (AIE)-mediated genetic mechanism for age-related gene regulation. Here, we report that this mechanism underlies the mysterious puberty-onset amelioration of abnormal bleeding seen in hemophilia B Leyden. Transgenic mice robustly mimicking the Leyden phenotype were constructed. Analysis of these animals indicated that ASE plays a central role in the puberty-onset amelioration of the disease. Human factor IX expression in these animals was reproducibly nullified by hypophysectomy, but nearly fully restored by administration of growth hormone, being consistent with the observed sex-independent recovery of factor IX expression. Ets1 was identified as the specific liver nuclear protein binding only to the functional ASE, G/CAGGAAG, and not to other Ets consensus elements. This study demonstrates the clinical relevance of the first discovered pubertyonset gene switch, the ASE/AIE-mediated regulatory mechanism.

Original languageEnglish (US)
Pages (from-to)7921-7926
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number19
DOIs
StatePublished - May 12 2009

Fingerprint

Hemophilia B
Puberty
Switch Genes
Factor IX
Homeostasis
Hypophysectomy
Nuclear Proteins
Protein Binding
Transgenic Mice
Growth Hormone
Hemorrhage
Phenotype
Gene Expression
Liver
Genes

Keywords

  • Factor IX
  • Gene switch
  • Growth hormone
  • Puberty
  • Sex hormone

ASJC Scopus subject areas

  • General

Cite this

An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden. / Kurachi, Sumiko; Huo, Jeffrey S.; Ameri, Afshin; Zhang, Kezhong; Yoshizawa, Akiyasu C.; Kurachi, Kotoku.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 19, 12.05.2009, p. 7921-7926.

Research output: Contribution to journalArticle

Kurachi, Sumiko ; Huo, Jeffrey S. ; Ameri, Afshin ; Zhang, Kezhong ; Yoshizawa, Akiyasu C. ; Kurachi, Kotoku. / An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 19. pp. 7921-7926.
@article{bda4af21990f4677862e735a5d588346,
title = "An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden",
abstract = "Regulation of age-related changes in gene expression underlies many diseases. We previously discovered the first puberty-onset gene switch, the age-related stability element (ASE)/age-related increase element (AIE)-mediated genetic mechanism for age-related gene regulation. Here, we report that this mechanism underlies the mysterious puberty-onset amelioration of abnormal bleeding seen in hemophilia B Leyden. Transgenic mice robustly mimicking the Leyden phenotype were constructed. Analysis of these animals indicated that ASE plays a central role in the puberty-onset amelioration of the disease. Human factor IX expression in these animals was reproducibly nullified by hypophysectomy, but nearly fully restored by administration of growth hormone, being consistent with the observed sex-independent recovery of factor IX expression. Ets1 was identified as the specific liver nuclear protein binding only to the functional ASE, G/CAGGAAG, and not to other Ets consensus elements. This study demonstrates the clinical relevance of the first discovered pubertyonset gene switch, the ASE/AIE-mediated regulatory mechanism.",
keywords = "Factor IX, Gene switch, Growth hormone, Puberty, Sex hormone",
author = "Sumiko Kurachi and Huo, {Jeffrey S.} and Afshin Ameri and Kezhong Zhang and Yoshizawa, {Akiyasu C.} and Kotoku Kurachi",
year = "2009",
month = "5",
day = "12",
doi = "10.1073/pnas.0902191106",
language = "English (US)",
volume = "106",
pages = "7921--7926",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "19",

}

TY - JOUR

T1 - An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden

AU - Kurachi, Sumiko

AU - Huo, Jeffrey S.

AU - Ameri, Afshin

AU - Zhang, Kezhong

AU - Yoshizawa, Akiyasu C.

AU - Kurachi, Kotoku

PY - 2009/5/12

Y1 - 2009/5/12

N2 - Regulation of age-related changes in gene expression underlies many diseases. We previously discovered the first puberty-onset gene switch, the age-related stability element (ASE)/age-related increase element (AIE)-mediated genetic mechanism for age-related gene regulation. Here, we report that this mechanism underlies the mysterious puberty-onset amelioration of abnormal bleeding seen in hemophilia B Leyden. Transgenic mice robustly mimicking the Leyden phenotype were constructed. Analysis of these animals indicated that ASE plays a central role in the puberty-onset amelioration of the disease. Human factor IX expression in these animals was reproducibly nullified by hypophysectomy, but nearly fully restored by administration of growth hormone, being consistent with the observed sex-independent recovery of factor IX expression. Ets1 was identified as the specific liver nuclear protein binding only to the functional ASE, G/CAGGAAG, and not to other Ets consensus elements. This study demonstrates the clinical relevance of the first discovered pubertyonset gene switch, the ASE/AIE-mediated regulatory mechanism.

AB - Regulation of age-related changes in gene expression underlies many diseases. We previously discovered the first puberty-onset gene switch, the age-related stability element (ASE)/age-related increase element (AIE)-mediated genetic mechanism for age-related gene regulation. Here, we report that this mechanism underlies the mysterious puberty-onset amelioration of abnormal bleeding seen in hemophilia B Leyden. Transgenic mice robustly mimicking the Leyden phenotype were constructed. Analysis of these animals indicated that ASE plays a central role in the puberty-onset amelioration of the disease. Human factor IX expression in these animals was reproducibly nullified by hypophysectomy, but nearly fully restored by administration of growth hormone, being consistent with the observed sex-independent recovery of factor IX expression. Ets1 was identified as the specific liver nuclear protein binding only to the functional ASE, G/CAGGAAG, and not to other Ets consensus elements. This study demonstrates the clinical relevance of the first discovered pubertyonset gene switch, the ASE/AIE-mediated regulatory mechanism.

KW - Factor IX

KW - Gene switch

KW - Growth hormone

KW - Puberty

KW - Sex hormone

UR - http://www.scopus.com/inward/record.url?scp=66049087865&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66049087865&partnerID=8YFLogxK

U2 - 10.1073/pnas.0902191106

DO - 10.1073/pnas.0902191106

M3 - Article

C2 - 19416882

AN - SCOPUS:66049087865

VL - 106

SP - 7921

EP - 7926

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 19

ER -