Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development

Govers, Anita M A P; Wiggers, Caroline R.M.; Boxtel, Ruben van; Mokrý, Michal; Nieuwenhuis, Edward E. S.; Creyghton, Menno P.; Bartels, Marije; Coffer, Paul J.

doi:10.1097/hs9.0000000000000270

Cited by 5 publications

(4 citation statements)

References 82 publications

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“…As expected, those with increased abundance were predominantly acetylation events (Figure 7D). For example, H3K27ac increased and H3K36me3 decreased after HDACi treatment as expected (Govers et al, 2019; Tharkar-Promod et al, 2018). Thus, these data offer molecular clues that link HDACi protein inhibition and transcriptomic and proteomics remodeling.…”

Section: Resultssupporting

confidence: 81%

Lineage-specific proteome remodeling of diverse lung cancer cells by targeted epigenetic inhibitors

Lin,

Sniezek,

Giglio

et al. 2024

Preprint

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Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogenous and dependent on factors such as the genetic background, metabolic state, and on-/off-target engagement of individual small-molecule drugs. To determine the mechanisms that drive these heterogeneous cellular responses, we quantified chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitor (HDACi) -treated cells derived from diverse genetic backgrounds. We utilized high-throughput sample multiplexed proteomics and integrated intelligent data acquisition methods to map proteomes of cancer cell lines in response to HDACi. We determined cell type-specific and ubiquitous cellular responses based on the quantification of 10,621 total proteins. We then established how coordinated remodeling of the proteome, transcriptome and chromatin state of HDACi treated cancer cells revealed convergent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) molecular phenotypes. HDACi- regulated proteins differ greatly across cell lines owing to heterogeneous molecular states of these cell lines. Finally, we demonstrated that HDACi treatment drove a highly cell-type specific response that may in part be explained by cell line-specific off-target drug engagement.

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Section: Resultssupporting

confidence: 81%

Lineage-specific proteome remodeling of diverse lung cancer cells by targeted epigenetic inhibitors

Lin,

Sniezek,

Giglio

et al. 2024

Preprint

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“…The genetic bases for different breathing patterns in different strains of mice at rest and in response to hypoxic and hypercapnic challenges have received extensive study ( Tankersley et al, 1994 ; Tankersley et al, 1998 ; Tankersley et al, 2000a ; Tankersley et al, 2000b ; Tankersley et al, 2000c ; Han and Strohl, 2000 ; Tankersley, 2000 ; Tankersley, 2001 ; Tankersley, 2003 ; Tankersley and Broman, 2004 ; Balbir et al, 2006 ; Gillombardo et al, 2012 ; Strohl et al, 2012 ) as have the genetic bases for the differences involve many neurochemical processes ( Tankersley et al, 2002a ; Tankersley et al, 2002b ; Tankersley et al, 2002c ; Price et al, 2003 ; Groeben et al, 2005 ; Yamauchi et al, 2008a ; Yamauchi et al, 2008b ; Moore et al, 2012 ; Moore et al, 2014 ), and structural features of respiratory structures, such as the carotid body ( Yamaguchi et al, 2003 ; Yamaguchi et al, 2006 ; Chai et al, 2011 ). The possibility that HDAC6 is a key player in the genetic factors that regulate ventilatory control processes per se , and those that respond to a hypoxic gas challenge, opens up intriguing avenues of research including those testing whether administration of selective HDAC6 inhibitors, such as CAY10603, Tubacin and Nexturastat ( Lu et al, 2017 ; Govers et al, 2019 ; Ma et al, 2019 ; Sanaei and Kavoosi, 2019 ; Sun et al, 2019 ), augment/stabilize ventilatory responses to hypoxic and/or hypercapnic challenges in mouse models, such as C57BL/6 mice ( Yamauchi et al, 2007 ; Yamauchi et al, 2008a ; Yamauchi et al, 2008b ; Yamauchi et al, 2008c ; Yamauchi et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Male histone deacetylase 6 (HDAC6) knockout mice have enhanced ventilatory responses to hypoxic challenge

Getsy,

Coffee,

Kelley

et al. 2024

Front. Physiol.

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Histone deacetylase 6 (HDAC6) is a class II histone deacetylase that is predominantly localized in the cytoplasm of cells. HDAC6 associates with microtubules and regulates acetylation of tubulin and other proteins. The possibility that HDAC6 participates in hypoxic signaling is supported by evidence that 1) hypoxic gas challenges cause microtubule depolymerization, 2) expression of hypoxia inducible factor alpha (HIF-1α) is regulated by microtubule alterations in response to hypoxia, and 3) inhibition of HDAC6 prevents HIF-1α expression and protects tissue from hypoxic/ischemic insults. The aim of this study was to address whether the absence of HDAC6 alters ventilatory responses during and/or after hypoxic gas challenge (10% O2, 90% N2 for 15 min) in adult male wildtype (WT) C57BL/6 mice and HDAC6 knock-out (KO) mice. Key findings were that 1) baseline values for frequency of breathing, tidal volume, inspiratory and expiratory times, and end expiratory pause were different between knock-out mice and wildtype mice, 2) ventilatory responses during hypoxic challenge were more robust in KO mice than WT mice for recorded parameters including, frequency of breathing, minute ventilation, inspiratory and expiratory durations, peak inspiratory and expiratory flows, and inspiratory and expiratory drives, and 3) responses upon return to room-air were markedly different in KO compared to WT mice for frequency of breathing, minute ventilation, inspiratory and expiratory durations, end expiratory pause (but not end inspiratory pause), peak inspiratory and expiratory flows, and inspiratory and expiratory drives. These data suggest that HDAC6 may have a fundamentally important role in regulating the hypoxic ventilatory response in mice.

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“…The genetic bases for different breathing patterns in mice at rest and in response to hypoxic and hypercapnic challenges in mouse strains have received extensive investigation 96-105 as have neurochemical processes, 66,67,88,89,106−108 and structural features of respiratory structures such as the carotid bodies. [109][110][111] The possibility that HDAC6 is a key player in the genetic factors that regulate breathing opens up intriguing avenues of research and especially testing whether selective HDAC6 inhibitors such as CAY10603, Tubacin and Nexturastat [112][113][114][115][116] augment and/or stabilize ventilatory responses to hypoxic and/or hypercapnic gas challenges in mouse models such as C57BL/6 mice. 63-65, 88,89 The results of the present study in male mice raises the question of whether female HDAC6 KO mice will also display many of the ventilatory features displayed by males and especially the ventilatory responses to hypoxia and those that occur upon return to room-air.…”

Section: Discussionmentioning

confidence: 99%

Male histone deacetylase 6 (HDAC6) knockout mice have enhanced ventilatory responses to hypoxic challenge

Getsy

Coffee

Kelley

et al. 2023

Preprint

View full text Add to dashboard Cite

Histone deacetylase 6 (HDAC6) is a class II histone deacetylase that is predominantly localized in the cytoplasm of cells. HDAC6 associates with microtubules, regulating acetylation of tubulin and other proteins. The possibility that HDAC6 participates in hypoxic signaling is supported by evidence that (1) hypoxic gas challenges cause microtubule depolymerization, (2) expression of hypoxia inducible factor alpha (HIF)-1α is regulated by microtubule alterations in response to hypoxia, and (3) inhibition of HDAC6 prevents HIF-1α expression and protects tissue from hypoxic/ischemic insults. The aim of this study was to address whether the absence of HDAC6 alters ventilatory responses during and/or after hypoxic gas challenges (10% O2, 90% N2 for 15 min) in adult male wild-type (WT) C57BL/6 mice and HDAC6 knock-out (KO) mice. Key findings were that (1) baseline values for frequency of breathing, tidal volume, inspiratory and expiratory times and end expiratory pause were different between KO mice and WT mice, (2) ventilatory responses during hypoxic challenge were more robust in KO mice than WT mice for parameters including frequency of breathing, minute ventilation, inspiratory and expiratory durations, peak inspiratory and expiratory flows, inspiratory and expiratory drives, and (3) responses upon return to room-air were markedly different in KO mice than WT mice for frequency of breathing, minute ventilation, inspiratory and expiratory durations, end expiratory (but not end inspiratory) pauses, peak inspiratory and expiratory flows, and inspiratory or expiratory drives. These data suggest that HDAC6 may have a fundamentally important role in regulating the neural responses to hypoxia.

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Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development

Abstract: Supplemental Digital Content is available in the text

Cited by 5 publications

References 82 publications

Lineage-specific proteome remodeling of diverse lung cancer cells by targeted epigenetic inhibitors

Lineage-specific proteome remodeling of diverse lung cancer cells by targeted epigenetic inhibitors

Male histone deacetylase 6 (HDAC6) knockout mice have enhanced ventilatory responses to hypoxic challenge

Male histone deacetylase 6 (HDAC6) knockout mice have enhanced ventilatory responses to hypoxic challenge

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