Mechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex

Song, Yun; Dagil, Lisbeth; Fairall, Louise; Robertson, Naomi; Wu, Mingxuan; Ragan, Timothy J.; Savva, Christos G.; Saleh, Almutasem; Morone, Nobuhiro; Kunze, Micha B. A.; Jamieson, Andrew G.; Cole, Philip A.; Hansen, D. Flemming; Schwabe, John W. R.

doi:10.1016/j.celrep.2020.01.091

Cited by 94 publications

(93 citation statements)

References 56 publications

(82 reference statements)

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“…Lsd1 acts, in the majority of cases, to remove mono-or di-methylation on lysine 4 of histone H3 (H3K4me1/me2) (7). It does so in a complex with Histone Deacetylase 1/2 (HDAC1/2) and Corepressor of REST (CoREST) in order to repress target genes (8)(9)(10)(11)(12)(13)(14). In other cases, however it has been shown that Lsd1 is involved in demethylation of H3K9 or H4K20 and can act as a transcriptional co-activator (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Histone demethylase Lsd1 is required for the differentiation of neural cells in the cnidarianNematostella vectensis

Gahan

Kouzel

Rentzsch

2020

Preprint

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The evolution of multicellularity was accompanied by the emergence of processes to regulate cell fate, identity and differentiation in a robust and faithful manner. Chromatin regulation has emerged as a key process in development and yet its contribution to the evolution of such processes is largely unexplored. Chromatin is regulated by a diverse set of proteins, which themselves are tightly regulated in order to play cell/ tissue-specific functions. Using the cnidarian Nematostella vectensis, a model for basal metazoans, we explore the function of one such chromatin regulator, Lysine specific demethylase 1 (Lsd1). We generated an endogenously tagged allele and show that the expression of NvLsd1 is developmentally regulated and higher in differentiated neural cells than their progenitors. We further show, using a CRISPR/Cas9 generated mutant that loss of NvLsd1 leads to several distinct developmental abnormalities. Strikingly, NvLsd1 loss leads to the almost complete loss of differentiated cnidocytes, cnidarian-specific neural cells, which we show to be the result of a cell-autonomous requirement for NvLsd1. Together this suggests that complex regulation of developmental processes by chromatin modifying proteins predates the split of the cnidarian and bilaterian lineages, approximately 600 million years ago, and may constitute an ancient feature of animal development.

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Section: Introductionmentioning

confidence: 99%

Histone demethylase Lsd1 is required for the differentiation of neural cells in the cnidarianNematostella vectensis

Gahan

Kouzel

Rentzsch

2020

Preprint

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“…An offline multi-angle light scattering (MALS) instrument is also available on the beamline. MALS provides an independent scattering-based measurement of the size, polydispersity and molecular weight of samples along with SAXS data (Behrens et al, 2020;Song et al, 2020).…”

Section: 32mentioning

confidence: 99%

Beamline B21: high-throughput small-angle X-ray scattering at Diamond Light Source

et al. 2020

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B21 is a small-angle X-ray scattering (SAXS) beamline with a bending magnet source in the 3 GeV storage ring at the Diamond Light Source Ltd synchrotron in the UK. The beamline utilizes a double multi-layer monochromator and a toroidal focusing optic to deliver 2 × 1012 photons per second to a 34 × 40 µm (FWHM) focal spot at the in-vacuum Eiger 4M (Dectris) detector. A high-performance liquid chromatography system and a liquid-handling robot make it possible to load solution samples into a temperature-controlled in-vacuum sample cell with a high level of automation. Alternatively, a range of viscous or solid materials may be loaded manually using a range of custom sample cells. A default scattering vector range from 0.0026 to 0.34 Å−1 and low instrument background make B21 convenient for measuring a wide range of biological macromolecules. The beamline has run a full user programme since 2013.

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“…When recruited to the CoREST complex, LSD1 catalyses the removal of activating mono- and di-methyl marks on nucleosomal H3K4 residues, resulting in transcriptional repression [ 169 , 170 ]. Studies have revealed a key functional interplay (or “crosstalk”) between HDAC and LSD1 within the complex, where the enzymes mutually influence each other’s activity via the CoREST protein [ 171 , 172 ]. HDAC inhibition has been shown to attenuate LSD1 activity [ 171 , 173 ], plus, synergistic effects of combined HDAC and LSD1 inhibition have been reported [ 174 , 175 , 176 , 177 ].…”

Section: Hdac Complex-selective Dual Inhibitorsmentioning

confidence: 99%

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

2020

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Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics—single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease.

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Mechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex

Cited by 94 publications

References 56 publications

Histone demethylase Lsd1 is required for the differentiation of neural cells in the cnidarianNematostella vectensis

Histone demethylase Lsd1 is required for the differentiation of neural cells in the cnidarianNematostella vectensis

Beamline B21: high-throughput small-angle X-ray scattering at Diamond Light Source

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

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