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Uppdaterad senast 2009-05-16
Projekt titel:
Effects of sex steroids on histone modification
Mingyan Hou Hallén, forskar-AT
Kort beskrivning: (max 2500 bokstäver)
Aim:
To study how sex steroids (testosterone and estrogens) affect modification of histones in androgen and/or
estrogen receptor rich tissues, e.g., liver, bone, uterus and thymus.
Background:
In both men and women, sex steroids (testosterone and estradiol) play a key role in health and well-being
as well as in sexual functioning. Testosterone can exert its effect on multiple levels either directly by
stimulation of the androgen receptor or via conversion in target-tissues to either DHT, the principal ligand
for the androgen receptor (AR) or estradiol (E2), the ligand for the estrogen receptors (ERs) α and β.
Epigenetic changes such as the covalent modification of histone residues are causally related to a broad
spectrum of human conditions spanning from monogenic disease to cancer and even multi-factorial
disorders. These modifications include acetylation and methylation of histone H3 lysines K9 and K14 and
are known to affect gene activation as well as repression. For example, trimethylation of H3K9
(H3K9Me3) is usually linked to gene repression.
In the developing mouse brain, higher levels of H3K9Me3 and H3K9/14 Ac are found in male compared
with female mice. Estrogen receptor transcription silencing due to hypermethylation is linked to the tumor
progression of breast, uterine, prostate and hepatocellular cancer. The aim of the proposed study is to
investigate the effect of testosterone and estradiol on the acetylation and methylation levels of histones in
organs with high expression of AR and ER such as liver, bone, uterus and thymus. These studies are
expected to increase the understanding of the mechanisms of action for sex steroids in sex different
steroid-dependent tissues and might result in the development of more specific sex steroid-based treatment
strategies associated with reduced side effects.
Studies:
1: To determine if there is sex differences in the levels of H3K9me3 and H3K9/14 Ac in different sex
steroid dependent tissues.
3: To determine if testosterone and/or estradiol modulate the levels of H3K9Me3 or H3K9/14Ac.
2: To evaluate if the H3K9Me3 and H3K9/14Ac levels in different organs are affected in ER or AR knock
out mice.
Representativa publikationer (max 3 stycken):
1: MAPKK-dependent growth factor-induced upregulation of P2Y2 receptors in vascular smooth muscle
cells. Mingyan Hou, Sebastian Möller, Lars Edvinsson and David Erlinge (Biochem and Biophys Res
Commun, 258, 648-652, 1999).
2: Cytokines induce upregulation of vascular P2Y2-receptor and increased mitogenic responses to UTP
and ATP. Mingyan Hou, Sebastian Möller, Lars Edvinsson, and David Erlinge (Arterioscler Thromb
Vasc Biol, 20, 2064-2069, 2000).
3: Nociceptin immunoreactivity and receptor mRNA in the human trigeminal ganglion. Mingyan Hou,
Rolf Uddman, Janos Tajti and Lars Edvinsson (Brain Res, 964, 179-186, 2003).
Forskningslab: Center for Bone Research
