Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation

Shuying He, Melinda K. Pirity, Wei Lin Wang, Louise Wolf, Bharesh K. Chauhan, Kveta Cveklova, Ernst R. Tamm, Ruth Ashery-Padan, Daniel Metzger, Akira Nakai, Pierre Chambon, Jiri Zavadil, Ales Cvekl

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Abstract

Background: Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs. Results. To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific A-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase II, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase II, for lens fiber cell denucleation and indirectly for retinal development. Conclusions. These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase II as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.

Original languageEnglish (US)
Article number21
JournalEpigenetics and Chromatin
Volume3
Issue number1
DOIs
StatePublished - 2010

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Chromatin Assembly and Disassembly
Lenses
Cell Differentiation
Enzymes
Deoxyribonucleases
Chromatin
Sucrose
Genes
High Mobility Group Proteins
Crystallins
Neural Stem Cells
Gene Targeting
Essential Genes
Cell Lineage
Amino Acid Substitution
Neuroglia

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology

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Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation. / He, Shuying; Pirity, Melinda K.; Wang, Wei Lin; Wolf, Louise; Chauhan, Bharesh K.; Cveklova, Kveta; Tamm, Ernst R.; Ashery-Padan, Ruth; Metzger, Daniel; Nakai, Akira; Chambon, Pierre; Zavadil, Jiri; Cvekl, Ales.

In: Epigenetics and Chromatin, Vol. 3, No. 1, 21, 2010.

Research output: Contribution to journalArticle

He, S, Pirity, MK, Wang, WL, Wolf, L, Chauhan, BK, Cveklova, K, Tamm, ER, Ashery-Padan, R, Metzger, D, Nakai, A, Chambon, P, Zavadil, J & Cvekl, A 2010, 'Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation', Epigenetics and Chromatin, vol. 3, no. 1, 21. https://doi.org/10.1186/1756-8935-3-21
He, Shuying ; Pirity, Melinda K. ; Wang, Wei Lin ; Wolf, Louise ; Chauhan, Bharesh K. ; Cveklova, Kveta ; Tamm, Ernst R. ; Ashery-Padan, Ruth ; Metzger, Daniel ; Nakai, Akira ; Chambon, Pierre ; Zavadil, Jiri ; Cvekl, Ales. / Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation. In: Epigenetics and Chromatin. 2010 ; Vol. 3, No. 1.
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abstract = "Background: Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs. Results. To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific A-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase II, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase II, for lens fiber cell denucleation and indirectly for retinal development. Conclusions. These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase II as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.",
author = "Shuying He and Pirity, {Melinda K.} and Wang, {Wei Lin} and Louise Wolf and Chauhan, {Bharesh K.} and Kveta Cveklova and Tamm, {Ernst R.} and Ruth Ashery-Padan and Daniel Metzger and Akira Nakai and Pierre Chambon and Jiri Zavadil and Ales Cvekl",
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T1 - Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation

AU - He, Shuying

AU - Pirity, Melinda K.

AU - Wang, Wei Lin

AU - Wolf, Louise

AU - Chauhan, Bharesh K.

AU - Cveklova, Kveta

AU - Tamm, Ernst R.

AU - Ashery-Padan, Ruth

AU - Metzger, Daniel

AU - Nakai, Akira

AU - Chambon, Pierre

AU - Zavadil, Jiri

AU - Cvekl, Ales

PY - 2010

Y1 - 2010

N2 - Background: Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs. Results. To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific A-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase II, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase II, for lens fiber cell denucleation and indirectly for retinal development. Conclusions. These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase II as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.

AB - Background: Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs. Results. To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific A-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase II, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase II, for lens fiber cell denucleation and indirectly for retinal development. Conclusions. These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase II as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.

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