β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture

Mahmood, Syed Raza; Xie, Xin; Said, Nadine Hosny El; Venit, Tomáš; Gunsalus, Kristin C.; Percipalle, Piergiorgio

doi:10.1038/s41467-021-25596-2

Cited by 44 publications

(31 citation statements)

References 70 publications

(92 reference statements)

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“…Interestingly, there were significant increases in the levels of BRG1 (Brahma related gene-1), MECP2 and MTA1 in Dex treated cells ( Supplementary Table S5 ). BRG1, an actin-binding, chromatin remodeling protein is well recognized to regulate glucocorticoid-induced gene expression ( Fryer and Archer, 1998 ; Hoffman et al, 2018 ; Mahmood et al, 2021 ). It is a catalytic subunit of the SWI/SNF multi-protein chromatin regulatory complex ( Khavari et al, 1993 ; Wilson and Roberts, 2011 ; Hodges et al, 2016 ) and is also involved in regulating the expression of actin cytoskeletal proteins through mechanisms including activation of SRF/MRTF-A dependent transcription ( Zhang et al, 2007 ; Zhou et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, it is becoming increasingly evident that several cell adhesive and certain actin-binding proteins, including actin, shuttle between the cytosolic and nuclear compartments to regulate transcriptional and chromatin remodeling activities ( Asp et al, 2002 ; Benmerah et al, 2003 ; Wang and Gilmore, 2003 ; Lundquist et al, 2014 ; Piccolo et al, 2014 ; Wang, 2014 ; Dupont, 2016 ; Chang et al, 2018 ; Klages-Mundt et al, 2018 ; Mahmood et al, 2021 ). Although several studies have examined the effects of glucocorticoids on the proteome and transcriptome profile of TM cells ( Lo et al, 2003 ; Nehme et al, 2009 ; Bollinger et al, 2012 ; Clark et al, 2013 ; Bermudez et al, 2017b ; Shan et al, 2017 ; Faralli et al, 2019 ), none of these have focused on characterizing the effects of glucocorticoids either on the cytoskeletome per se or on the nuclear fraction proteome of TM cells.…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoids Preferentially Influence Expression of Nucleoskeletal Actin Network and Cell Adhesive Proteins in Human Trabecular Meshwork Cells

Bachman

Maddala

Chakraborty

et al. 2022

Front. Cell Dev. Biol.

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Clinical use of glucocorticoids is associated with increased intraocular pressure (IOP), a major risk factor for glaucoma. Glucocorticoids have been reported to induce changes in actin cytoskeletal organization, cell adhesion, extracellular matrix, fibrogenic activity, and mechanical properties of trabecular meshwork (TM) tissue, which plays a crucial role in aqueous humor dynamics and IOP homeostasis. However, we have a limited understanding of the molecular underpinnings regulating these myriad processes in TM cells. To understand how proteins, including cytoskeletal and cell adhesion proteins that are recognized to shuttle between the cytosolic and nuclear regions, influence gene expression and other cellular activities, we used proteomic analysis to characterize the nuclear protein fraction of dexamethasone (Dex) treated human TM cells. Treatment of human TM cells with Dex for 1, 5, or 7 days led to consistent increases (by ≥ two-fold) in the levels of various actin cytoskeletal regulatory, cell adhesive, and vesicle trafficking proteins. Increases (≥two-fold) were also observed in levels of Wnt signaling regulator (glypican-4), actin-binding chromatin modulator (BRG1) and nuclear actin filament depolymerizing protein (MICAL2; microtubule-associated monooxygenase, calponin and LIM domain containing), together with a decrease in tissue plasminogen activator. These changes were independently further confirmed by immunoblotting analysis. Interestingly, deficiency of BRG1 expression blunted the Dex-induced increases in the levels of some of these proteins in TM cells. In summary, these findings indicate that the widely recognized changes in actin cytoskeletal and cell adhesive attributes of TM cells by glucocorticoids involve actin regulated BRG1 chromatin remodeling, nuclear MICAL2, and glypican-4 regulated Wnt signaling upstream of the serum response factor/myocardin controlled transcriptional activity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glucocorticoids Preferentially Influence Expression of Nucleoskeletal Actin Network and Cell Adhesive Proteins in Human Trabecular Meshwork Cells

Bachman

Maddala

Chakraborty

et al. 2022

Front. Cell Dev. Biol.

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“…Changes in 3D genome organization arise naturally over the course of development and differentiation [ 5 – 10 ] or can be triggered by genetic perturbation of proteins involved in genome regulation [ 11 – 13 ]. In order to investigate the mechanisms driving transcriptional change upon compartment-switching in both these scenarios, we utilized two published datasets containing HiC, ATAC-Seq, ChIP-Seq, and RNA-Seq data.…”

Section: Resultsmentioning

confidence: 99%

β-actin mediated H3K27ac changes demonstrate the link between compartment switching and enhancer-dependent transcriptional regulation

et al. 2023

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Background Recent work has demonstrated that three-dimensional genome organization is directly affected by changes in the levels of nuclear cytoskeletal proteins such as β-actin. The mechanisms which translate changes in 3D genome structure into changes in transcription, however, are not fully understood. Here, we use a comprehensive genomic analysis of cells lacking nuclear β-actin to investigate the mechanistic links between compartment organization, enhancer activity, and gene expression. Results Using HiC-Seq, ATAC-Seq, and RNA-Seq, we first demonstrate that transcriptional and chromatin accessibility changes observed upon β-actin loss are highly enriched in compartment-switching regions. Accessibility changes within compartment switching genes, however, are mainly observed in non-promoter regions which potentially represent distal regulatory elements. Our results also show that β-actin loss induces widespread accumulation of the enhancer-specific epigenetic mark H3K27ac. Using the ABC model of enhancer annotation, we then establish that these epigenetic changes have a direct impact on enhancer activity and underlie transcriptional changes observed upon compartment switching. A complementary analysis of fibroblasts undergoing reprogramming into pluripotent stem cells further confirms that this relationship between compartment switching and enhancer-dependent transcriptional change is not specific to β-actin knockout cells but represents a general mechanism linking compartment-level genome organization to gene expression. Conclusions We demonstrate that enhancer-dependent transcriptional regulation plays a crucial role in driving gene expression changes observed upon compartment-switching. Our results also reveal a novel function of nuclear β-actin in regulating enhancer function by influencing H3K27 acetylation levels.

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“…After the transfer, total protein was imaged using Bio Rad ChemiDoc imager under the stain free blot setting for normalization purposes. Total protein transferred to the blot membrane, rather than the traditional use of housekeeping genes such as beta actin and glyceraldehyde phosphate dehydrogenase, was used to normalize protein expression because studies show that “housekeeping” genes are often altered in processes associated with neurodegenerative diseases ( Kish et al, 1998 ; Mahmood et al, 2021 ). Therefore, our results are presented as the expression levels of the target gene compared total protein transferred to the blot membrane, a more accurate representation of protein expression in any given lysate.…”

Section: Methodsmentioning

confidence: 99%

Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study

Fields

Swinton

Sundermann

et al. 2022

Front. Aging Neurosci.

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People with HIV (PWH) continue to suffer from dysfunction of the central nervous system, as evidenced by HIV-associated neurocognitive disorder (HAND), despite antiretroviral therapy and suppressed viral loads. As PWH live longer they may also be at risk of age-related neurodegenerative diseases such Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). The complement system is associated with deposition of AD-related proteins such as beta amyloid (Aβ), neuroinflammation, and neurological dysfunction in PWH. Complement component 3 (C3) is a key protagonist in the complement cascade and complement factor H (CFH) is an antagonist of C3 activity. We investigated the relationship between C3 and CFH levels in the brain and Aβ plaques and neurological dysfunction in 22 PWH. We analyzed by immunoblot C3 and CFH protein levels in frontal cortex (FC) and cerebellum (CB) brain specimens from PWH previously characterized for Aβ plaque deposition. C3 and CFH protein levels were then correlated with specific cognitive domains. C3 protein levels in the FC were significantly increased in brains with Aβ plaques and in brains with HAND compared to controls. In the CB, C3 levels trended higher in brains with Aβ plaques. Overall C3 protein levels were significantly higher in the FC compared to the CB, but the opposite was true for CFH, having significantly higher levels of CFH protein in the CB compared to the FC. However, only CFH in the FC showed significant correlations with specific domains, executive function and motor performance. These findings corroborate previous results showing that complement system proteins are associated with HAND and AD neuropathogenesis.

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β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture

Cited by 44 publications

References 70 publications

Glucocorticoids Preferentially Influence Expression of Nucleoskeletal Actin Network and Cell Adhesive Proteins in Human Trabecular Meshwork Cells

Glucocorticoids Preferentially Influence Expression of Nucleoskeletal Actin Network and Cell Adhesive Proteins in Human Trabecular Meshwork Cells

β-actin mediated H3K27ac changes demonstrate the link between compartment switching and enhancer-dependent transcriptional regulation

Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study

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