LBR and Lamin A/C Sequentially Tether Peripheral Heterochromatin and Inversely Regulate Differentiation

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• 作者：Irina Solovei¹ ; Audrey S. Wang² ; ³ ; Katharina Thanisch¹ ; Christine S. Schmidt¹ ; Stefan Krebs⁴ ; Monika Zwerger⁵ ; Tatiana V. Cohen⁶ ; Didier Devys⁷ ; Roland Foisner⁸ ; Leo Peichl⁹ ; Harald Herrmann⁵ ; Helmut Blum⁴ ; Dieter Engelkamp¹⁰ ; Colin L. Stewart² ; ³ ; ^{colin.stewart@imb.a-star.edu.sg} ; Heinrich Leonhardt¹ ; ^{h.leonhardt@lmu.de} ; Boris Joffe¹ ; ^{boris.joffe@lmu.de}
• 刊名：Cell
• 出版年：2013
• 出版时间：31 January, 2013
• 年：2013
• 卷：152
• 期：3
• 页码：584-598
• 全文大小：4017 K

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Summary

Eukaryotic cells have a layer of heterochromatin at the nuclear periphery. To investigate mechanisms regulating chromatin distribution, we analyzed heterochromatin organization in different tissues and species, including mice with mutations in the lamin B receptor (Lbr) and lamin A (Lmna) genes that encode nuclear envelope (NE) proteins. We identified LBR- and lamin-A/C-dependent mechanisms tethering heterochromatin to the NE. The two tethers are sequentially used during cellular differentiation and development: first the LBR- and then the lamin-A/C-dependent tether. The absence of both LBR and lamin A/C leads to loss of peripheral heterochromatin and an inverted architecture with heterochromatin localizing to the nuclear interior. Myoblast transcriptome analyses indicated that selective disruption of the LBR- or lamin-A-dependent heterochromatin tethers have opposite effects on muscle gene expression, either increasing or decreasing, respectively. These results show how changes in NE composition contribute to regulating heterochromatin positioning, gene expression, and cellular differentiation during development.