Chromatin remodeling and histone modifications in developmental gene regulation by thyroid hormone
Yun-Bo Shi*
Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
Thyroid hormone (TH) plays an important role during postembryonic development in vertebrates, a period around birth in mammals or of metamorphic transformation in amphibians. TH regulates gene transcription through nuclear TH receptors (TRs) that bind to specific DNA sequences in target genes. TRs can repress or activate TH-inducible genes in the absence or presence of TH, respectively. We have been investigating the roles of TRs during development by using Xenopus metamorphosis as a model. We have shown previously that TH plays a causative role in amphibian metamorphosis via binding to TRs. More recently, we have analyzed the function of endogenous TRα, which, unlike the second TR or TRβ, is highly expressed prior to the synthesis of endogenous TH, by using TALEN (transcription activator-like effector nuclease)-mediated gene knockout approach. We show that TRα knockout has no effect on embryogenesis but leads to accelerated growth and development of the tadpoles, indicating that unliganded TRα controls both premetamorphic tadpole growth and metamorphic timing. On the other hand, such knockout animals are also resistant to exogenous TH treatment and have delayed natural metamorphosis, demonstrating a critical role of TRα in mediating TH effect on metamorphosis. Toward understanding the underlying mechanisms, we have shown that unliganded TR recruits histone deacetylase (HDAC)-containing N-CoR/SMRT complexes in premetamorphic tadpoles while liganded TR recruits histone modification complexes during metamorphosis. We have further shown that liganded TR induces histone modifications and the removal of core histones at target promoters in vivo. Collectively, our data indicate that TR recruits histone-modification complexes to alter the dynamics of nucleosomal structure and histone modifications at the target genes in a TH dependent manner, thereby regulating growth and metamorphic timing in premetamorphic tadpoles and the rate of metamorphic progression during metamorphosis.
Key Words: Xenopus, thyroid hormone receptor, histone modification, epigenetics, metamorphosis, chromatin remodeling
Yun-Bo Shi*
Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
Thyroid hormone (TH) plays an important role during postembryonic development in vertebrates, a period around birth in mammals or of metamorphic transformation in amphibians. TH regulates gene transcription through nuclear TH receptors (TRs) that bind to specific DNA sequences in target genes. TRs can repress or activate TH-inducible genes in the absence or presence of TH, respectively. We have been investigating the roles of TRs during development by using Xenopus metamorphosis as a model. We have shown previously that TH plays a causative role in amphibian metamorphosis via binding to TRs. More recently, we have analyzed the function of endogenous TRα, which, unlike the second TR or TRβ, is highly expressed prior to the synthesis of endogenous TH, by using TALEN (transcription activator-like effector nuclease)-mediated gene knockout approach. We show that TRα knockout has no effect on embryogenesis but leads to accelerated growth and development of the tadpoles, indicating that unliganded TRα controls both premetamorphic tadpole growth and metamorphic timing. On the other hand, such knockout animals are also resistant to exogenous TH treatment and have delayed natural metamorphosis, demonstrating a critical role of TRα in mediating TH effect on metamorphosis. Toward understanding the underlying mechanisms, we have shown that unliganded TR recruits histone deacetylase (HDAC)-containing N-CoR/SMRT complexes in premetamorphic tadpoles while liganded TR recruits histone modification complexes during metamorphosis. We have further shown that liganded TR induces histone modifications and the removal of core histones at target promoters in vivo. Collectively, our data indicate that TR recruits histone-modification complexes to alter the dynamics of nucleosomal structure and histone modifications at the target genes in a TH dependent manner, thereby regulating growth and metamorphic timing in premetamorphic tadpoles and the rate of metamorphic progression during metamorphosis.
Key Words: Xenopus, thyroid hormone receptor, histone modification, epigenetics, metamorphosis, chromatin remodeling