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KMT1/Suv39 methyltransferase family regulates peripheral heterochromatin tethering via histone and non-histone protein methylations

Radhika Arasala Rao, Alhad Ashok Ketkar, Neelam Kedia, Vignesh K Krishnamoorthy, Vairavan Lakshmanan, Pankaj Kumar, Abhishek Mohanty, Shilpa Dilip Kumar, Sufi O Raja, View ORCID ProfileAkash Gulyani, ChandraPrakash Chaturvedi, Marjorie Brand, Dasaradhi Palakodeti, View ORCID ProfileShravanti Rampalli
doi: https://doi.org/10.1101/240952
Radhika Arasala Rao
1Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
3Sastra University, Tirumalaisamudram, Thanjavur-613 401, TamilNadu, India
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Alhad Ashok Ketkar
1Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Neelam Kedia
1Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Vignesh K Krishnamoorthy
1Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Vairavan Lakshmanan
2Technologies for the Advancement of Science, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
3Sastra University, Tirumalaisamudram, Thanjavur-613 401, TamilNadu, India
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Pankaj Kumar
1Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Abhishek Mohanty
1Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Shilpa Dilip Kumar
2Technologies for the Advancement of Science, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Sufi O Raja
2Technologies for the Advancement of Science, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Akash Gulyani
2Technologies for the Advancement of Science, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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ChandraPrakash Chaturvedi
5Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, Uttar Pradesh, India
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Marjorie Brand
4Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Mailbox 511, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada
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Dasaradhi Palakodeti
2Technologies for the Advancement of Science, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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Shravanti Rampalli
1Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK Campus, Bellary Road, Bangalore-560065, Karnataka, India
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  • ORCID record for Shravanti Rampalli
  • For correspondence: shravantird@instem.res.in
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Abstract

Euchromatic histone methyltransferases (EHMTs), members of the KMT1 family, methylate histone and non-histone proteins. Here we uncover a novel role for EHMTs in regulating heterochromatin anchorage to the nuclear periphery (NP) via non-histone (LaminB1) methylations. We show that EHMTs methylates and stabilizes LaminB1 (LMNB1), which associates with the H3K9me2-marked peripheral heterochromatin. Loss of LMNB1 methylation or EHMTs abrogates the heterochromatin anchorage from the NP. We further demonstrate that the loss of EHMTs induces many hallmarks of aging including global reduction of H3K27methyl marks along with altered nuclear-morphology. Consistent with this, we observed a gradual depletion of EHMTs, which correlates with loss of methylated LMNB1 and peripheral heterochromatin in aging human fibroblasts. Restoration of EHMT expression reverts peripheral heterochromatin defect in aged cells. Collectively our work elucidates a new mechanism by which EHMTs regulate heterochromatin domain organization and reveals their impact on fundamental changes associated with the intrinsic aging process.

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Posted January 24, 2019.
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KMT1/Suv39 methyltransferase family regulates peripheral heterochromatin tethering via histone and non-histone protein methylations
Radhika Arasala Rao, Alhad Ashok Ketkar, Neelam Kedia, Vignesh K Krishnamoorthy, Vairavan Lakshmanan, Pankaj Kumar, Abhishek Mohanty, Shilpa Dilip Kumar, Sufi O Raja, Akash Gulyani, ChandraPrakash Chaturvedi, Marjorie Brand, Dasaradhi Palakodeti, Shravanti Rampalli
bioRxiv 240952; doi: https://doi.org/10.1101/240952
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KMT1/Suv39 methyltransferase family regulates peripheral heterochromatin tethering via histone and non-histone protein methylations
Radhika Arasala Rao, Alhad Ashok Ketkar, Neelam Kedia, Vignesh K Krishnamoorthy, Vairavan Lakshmanan, Pankaj Kumar, Abhishek Mohanty, Shilpa Dilip Kumar, Sufi O Raja, Akash Gulyani, ChandraPrakash Chaturvedi, Marjorie Brand, Dasaradhi Palakodeti, Shravanti Rampalli
bioRxiv 240952; doi: https://doi.org/10.1101/240952

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