SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies

Boulanger, Mathias; Chakraborty, Mehuli; Tempé, Denis; Piechaczyk, Marc; Bossis, Guillaume

doi:10.3390/molecules26040828

Cited by 59 publications

(55 citation statements)

References 295 publications

(644 reference statements)

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“…Transcription factors are among the most frequently detected targets of sumoylation [ 52 , 53 ]. Unlike in S. cerevisiae , where inactivation of SUMO is lethal [ 34 ], sumO can be deleted in Aspergilli and Schizosaccharomyces pombe giving rise to drastic phenotypical changes [ 33 , 34 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

The bZIP Transcription Factor HapX Is Post-Translationally Regulated to Control Iron Homeostasis in Aspergillus fumigatus

López‐Berges

Scheven

Hortschansky

et al. 2021

IJMS

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The airborne fungus Aspergillus fumigatus causes opportunistic infections in humans with high mortality rates in immunocompromised patients. Previous work established that the bZIP transcription factor HapX is essential for virulence via adaptation to iron limitation by repressing iron-consuming pathways and activating iron acquisition mechanisms. Moreover, HapX was shown to be essential for transcriptional activation of vacuolar iron storage and iron-dependent pathways in response to iron availability. Here, we demonstrate that HapX has a very short half-life during iron starvation, which is further decreased in response to iron, while siderophore biosynthetic enzymes are very stable. We identified Fbx22 and SumO as HapX interactors and, in agreement, HapX post-translational modifications including ubiquitination of lysine161, sumoylation of lysine242 and phosphorylation of threonine319. All three modifications were enriched in the immediate adaptation from iron-limiting to iron-replete conditions. Interfering with these post-translational modifications, either by point mutations or by inactivation, of Fbx22 or SumO, altered HapX degradation, heme biosynthesis and iron resistance to different extents. Consistent with the need to precisely regulate HapX protein levels, overexpression of hapX caused significant growth defects under iron sufficiency. Taken together, our results indicate that post-translational regulation of HapX is important to control iron homeostasis in A. fumigatus.

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Section: Discussionmentioning

confidence: 99%

The bZIP Transcription Factor HapX Is Post-Translationally Regulated to Control Iron Homeostasis in Aspergillus fumigatus

López‐Berges

Scheven

Hortschansky

et al. 2021

IJMS

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“…In addition to SSTFs, multiple components of the general transcription machinery, including subunits of the general transcription factors (GTFs) and RNA polymerases (RNAPs) I, II, and III, have been identified as SUMO targets, but the effects of SUMO modification of these proteins have been examined in only a few cases [ 2 , 6 , 9 , 23 ]. Under normal growth conditions, sumoylation of the yeast RNAPIII subunit Rpc82 promotes assembly and recruitment of RNAPIII to tRNA-encoding genes, whereas under conditions of stress or nutrient depletion, under which tRNA transcription is reduced, multiple RNAPIII subunits become unsumoylated [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Dynamic sumoylation of promoter-bound general transcription factors facilitates transcription by RNA polymerase II

et al. 2021

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Transcription-related proteins are frequently identified as targets of sumoylation, including multiple subunits of the RNA polymerase II (RNAPII) general transcription factors (GTFs). However, it is not known how sumoylation affects GTFs or whether they are sumoylated when they assemble at promoters to facilitate RNAPII recruitment and transcription initiation. To explore how sumoylation can regulate transcription genome-wide, we performed SUMO ChIP-seq in yeast and found, in agreement with others, that most chromatin-associated sumoylated proteins are detected at genes encoding tRNAs and ribosomal proteins (RPGs). However, we also detected 147 robust SUMO peaks at promoters of non-ribosomal protein-coding genes (non-RPGs), indicating that sumoylation also regulates this gene class. Importantly, SUMO peaks at non-RPGs align specifically with binding sites of GTFs, but not other promoter-associated proteins, indicating that it is GTFs specifically that are sumoylated there. Predominantly, non-RPGs with SUMO peaks are among the most highly transcribed, have high levels of TFIIF, and show reduced RNAPII levels when cellular sumoylation is impaired, linking sumoylation with elevated transcription. However, detection of promoter-associated SUMO by ChIP might be limited to sites with high levels of substrate GTFs, and promoter-associated sumoylation at non-RPGs may actually be far more widespread than we detected. Among GTFs, we found that TFIIF is a major target of sumoylation, specifically at lysines 60/61 of its Tfg1 subunit, and elevating Tfg1 sumoylation resulted in decreased interaction of TFIIF with RNAPII. Interestingly, both reducing promoter-associated sumoylation, in a sumoylation-deficient Tfg1-K60/61R mutant strain, and elevating promoter-associated SUMO levels, by constitutively tethering SUMO to Tfg1, resulted in reduced RNAPII occupancy at non-RPGs. This implies that dynamic GTF sumoylation at non-RPG promoters, not simply the presence or absence of SUMO, is important for maintaining elevated transcription. Together, our findings reveal a novel mechanism of regulating the basal transcription machinery through sumoylation of promoter-bound GTFs.

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“…The majority of these studies have concluded that sumoylation generally inhibits adipogenic transcription factors. This view has been standing for many years, but recent systematic large-scale studies have revealed that SUMO not only represses but can also promote transcription, depending on the cellular system and the physiological context (Boulanger et al, 2021;Chymkowitch et al, 2015b). Systematic analysis of the dynamics of SUMO-regulated gene expression in differentiating adipocytes has never been performed.…”

Section: Discussionmentioning

confidence: 99%

Waves of sumoylation support transcription dynamics during adipocyte differentiation

Hendriks

Gras

et al. 2021

Preprint

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Tight control of gene expression networks required for adipose tissue formation and plasticity is essential for adaptation to energy needs and environmental cues. However, little is known about the mechanisms that orchestrate the dramatic transcriptional changes leading to adipocyte differentiation. We investigated the regulation of nascent transcription by SUMO during adipocyte differentiation using SLAMseq and ChIPseq. We discovered that SUMO has a dual function in differentiation; it supports the initial downregulation of pre-adipocyte-specific genes, while it promotes the establishment of the mature adipocyte transcriptional program. By characterizing sumoylome dynamics in differentiating adipocytes by mass spectrometry, we found that sumoylation of chromatin modifiers and specific transcription factors like Pparγ/RXR promotes the transcription of adipogenic genes. Our data demonstrate that the sumoylation pathway coordinates the rewiring of transcriptional networks required for formation of functional adipocytes.

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SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies

Cited by 59 publications

References 295 publications

The bZIP Transcription Factor HapX Is Post-Translationally Regulated to Control Iron Homeostasis in Aspergillus fumigatus

The bZIP Transcription Factor HapX Is Post-Translationally Regulated to Control Iron Homeostasis in Aspergillus fumigatus

Dynamic sumoylation of promoter-bound general transcription factors facilitates transcription by RNA polymerase II

Waves of sumoylation support transcription dynamics during adipocyte differentiation

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