SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy

Wang, Zhentian; Hausmann, Simone; Lyu, Ruitu; Li, Tie Mei; Lofgren, Shane; Flores, Natasha; Fuentes, Mary E.; Caporicci, Marcello; Yang, Zihui; Meiners, Matthew J.; Cheek, Marcus A.; Howard, Sarah A.; Zhang, Lichao; Elias, Joshua E.; Kim, Michael P.; Maitra, Anirban; Wang, Huamin; Bassik, Michael C.; Keogh, Michael Christopher; Sage, Julien; Gozani, Or; Mazur, Paweł K.

doi:10.1016/j.ccell.2020.04.014

Cited by 57 publications

(63 citation statements)

References 74 publications

(91 reference statements)

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“…SETD5 upregulation has recently been linked to MEK resistance in PDAC (Z. Wang et al, 2020). The most recurrent driver, Foxp1 , was present in 26 of the metastatic lesions from liver, lung and lymph nodes, suggesting that this driver plays a role in both establishing and promoting pancreatic cancer progression in the SB model.…”

Section: Resultsmentioning

confidence: 99%

Insertional mutagenesis defines drivers and evolutionary relationships in pancreatic cancer metastasis

Govindaraju

Maurin

Newberg

et al. 2020

Preprint

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Metastasis is a defining feature of pancreatic cancer, impacting patient quality of life and therapeutic outcomes. While recurrent mutations in KRAS and TP53 play important roles in primary tumor development and persist in metastases, the contributions of other genes to the metastatic process is understudied. Here, we define a network of metastasis-promoting genes and uncover positively selected genes in metastatic lesions from our Sleeping Beauty mouse model of pancreatic cancer using our recently described SB Driver Analysis statistical pipeline. We show that loss of single genes DLG1, PARD3, PKP4 and PTPRK promote pancreas cancer progression in a context-specific manner. Finally, we define clonal and sub-clonal insertion events that distinguish primary and individual metastatic tumors and use single cell sequencing to gain insight into the evolutionary relationships between sub-regions of primary pancreatic tumors and related metastases, which has important implications for pancreatic disease progression and therapeutic opportunities for patients.

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Section: Resultsmentioning

confidence: 99%

Insertional mutagenesis defines drivers and evolutionary relationships in pancreatic cancer metastasis

Govindaraju

Maurin

Newberg

et al. 2020

Preprint

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“…Multiple histone deacetylases (HDACs) have been shown to control expression of stress response genes within subtelomeric regions and are key regulators of the repressive chromatin environment at subtelomeres (26)(27)(28)(29). Orthologs of Set4 in other organisms and the yeast protein Set3 are known to interact with or otherwise regulate the activity of HDACs in different chromatin environments (7,9,19,21,50,51). Thus, we hypothesized that Set4 may play a similar role at subtelomeric regions in yeast.…”

Section: Set4 Maintains Histone Acetylation Levels At Stress Response Genes Within Subtelomeric Regionsmentioning

confidence: 99%

Set4 coordinates the activity of histone deacetylases and regulates stress-responsive gene expression within subtelomeric regions in yeast

Jethmalani

Tran

Jaiswal

et al. 2021

Preprint

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The yeast chromatin protein Set4 is a member of the Set3-subfamily of SET domain proteins which play critical roles in the regulation of gene expression in diverse developmental and environmental contexts, although they appear to lack methyltransferase activity. The molecular functions of Set4 are relatively unexplored, likely due to its low abundance in standard growth conditions. We previously reported that Set4 promotes survival during oxidative stress and regulates expression of stress response genes via stress-dependent chromatin localization. In this study, global gene expression analysis and investigation of histone modification status has revealed a role for Set4 in maintaining gene repressive mechanisms within yeast subtelomeres under both normal and stress conditions. We show that Set4 works in a partially overlapping pathway to the SIR complex and the histone deacetylase Rpd3 to maintain proper levels of histone acetylation and expression of stress response genes encoded in subtelomeres. This role for Set4 is particularly critical for cells under hypoxic conditions, and the loss of Set4 decreases cell fitness and cell wall integrity in hypoxia. These findings uncover a new regulator of subtelomeric chromatin that is key to stress defense pathways and demonstrate a function for yeast Set4 in regulating repressive, heterochromatin-like environments.

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“…These included peptides corresponding to NCoR (also known as NCoR1), SMRT (also known as NCoR2), TBL1 (also known as TBL1X), TBLR1, SKI, and HDAC3 (Fig. 1k, blue solid circle) which is known to interact with SETD5 27,30,38 suggesting that SETD5 associates with this corepressor complex independent of its SET domain but dependent on the domain that was required for inhibition of adipogenesis. This is consistent with previous data showing a larger C-terminal deletion of SETD5 disrupts its interaction with HDAC3 27,30,38 .…”

Section: Setd5 Associates With Ncor-hdac3 Co-repressor Complex and Rementioning

confidence: 99%

“…Among them, SETD5 is a potential histone methyltransferase whose gene expression declines during the first 48 hrs of adipogenesis 21 . Recent genetic studies reported loss-of function mutations in SETD5 in patients with intellectual disability 24,25,26 and studies in Setd5 mutant mice suggested roles of SETD5 in neuronal development, however, whether it actually contains histone methyltransferase activity has been controversial and could be context dependent 27,28,29,30 .…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis

Matsumura

Itô

Yajima

et al. 2021

Preprint

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Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.

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SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy

Cited by 57 publications

References 74 publications

Insertional mutagenesis defines drivers and evolutionary relationships in pancreatic cancer metastasis

Insertional mutagenesis defines drivers and evolutionary relationships in pancreatic cancer metastasis

Set4 coordinates the activity of histone deacetylases and regulates stress-responsive gene expression within subtelomeric regions in yeast

Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis

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