Transglutaminase 2 mediates transcriptional regulation through BAF250a polyamination

Kim, Hyo Jun; Lee, Jin Haeng; Cho, Sung Yup; Jeon, Ju Hong; Kim, In Gyu

doi:10.1007/s13258-021-01055-6

Cited by 9 publications

(11 citation statements)

References 37 publications

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“…TG2 is primarily a cytosolic protein, but it can also be externalized and deposited into the extracellular matrix (ECM) [25] and localize to the nucleus where it is found in the chromatin fraction [26]. Given the fact that TG2 is found in the nucleus, it is not surprising that its ability to regulate gene transcription is well-documented across many cell types, however this data is lacking in astrocytes, and specific mechanisms of transcriptional regulation have not been fully elucidated [21,[27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Deletion of transglutaminase 2 from astrocytes significantly improves their ability to promote neurite outgrowth on an inhibitory matrix

Emerson

Delgado

Girardi

et al. 2023

Preprint

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AAstrocytes are the primary support cells of the central nervous system (CNS) that help maintain the energetic requirements and homeostatic environment of neurons. CNS injury causes astrocytes to take on reactive phenotypes with altered overall function that can range from supportive to harmful for recovering neurons. The characterization of reactive astrocyte populations is a rapidly developing field, and the underlying factors and signaling pathways governing which type of reactive phenotype that astrocytes take on is poorly understood. Our previous studies suggest that transglutaminase 2 (TG2) has an important role in determining the astrocytic response to injury. TG2 is upregulated in astrocytes across multiple injury models, and selectively deleting TG2 from astrocytes improves functional outcomes after CNS injury and causes widespread changes in gene regulation, which is associated with its nuclear localization. The underlying molecular mechanisms by which TG2 causes these functional changes are unknown, and its interactions in the nucleus of astrocytes has not yet been described. To begin to understand how TG2 impacts astrocytic function, we used a neuron-astrocyte co-culture paradigm to compare the effects of TG2-/- and wild type (WT) astrocytes on neurite outgrowth and synapse formation. We assayed neurons on both a growth-supportive substrate and an injury-simulating matrix comprised of inhibitory chondroitin sulfate proteoglycans (CSPGs). Compared to WT astrocytes, TG2-/- astrocytes supported neurite outgrowth to a significantly greater extent only on the CSPG matrix, while synapse formation assays showed mixed results depending on the pre- and post-synaptic markers analyzed. We hypothesize that TG2 regulates the supportive functions of astrocytes in injury conditions by modulating the expression of a wide range of genes through interactions with transcription factors and transcription complexes. Based on results of a previous yeast two-hybrid screen for TG2 interactors, we further investigated the interaction of TG2 with Zbtb7a, a ubiquitously expressed transcription factor. Co-immunoprecipitation and colocalization analyses confirmed the interaction of TG2 and Zbtb7a in the nucleus of astrocytes. Genetic overexpression or knockdown of Zbtb7a levels in TG2-/- and WT astrocytes revealed that Zbtb7a robustly influenced astrocytic morphology and the ability of astrocytes to support neuronal outgrowth, which was significantly modulated by the presence of TG2. These findings support our hypothesis that astrocytic TG2 acts as a transcriptional regulator to influence astrocytic function, with greater influence under injury conditions that increase its expression, and Zbtb7a likely contributes to the overall effects observed with astrocytic TG2 deletion.

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Section: Introductionmentioning

confidence: 99%

Deletion of transglutaminase 2 from astrocytes significantly improves their ability to promote neurite outgrowth on an inhibitory matrix

Emerson

Delgado

Girardi

et al. 2023

Preprint

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“…To begin to elucidate the mechanisms underlying the effects of VA4 treatment, we tested whether VA4 modulates the interaction of TG2 and Zbtb7a, a transcription factor that we previously identified as a TG2 interactor (Emerson et al 2023). Based on results of our IP experiments, and the established roles of TG2 for regulating gene expression (Elahi et al 2021, Filiano et al 2008, Gundemir et al 2013, Kim et al 2021, McConoughey et al 2010, Monteagudo et al 2018, Rossin et al 2023, and Zbtb7a for regulating chromatin accessibility (Pittol et al 2018, Monteagudo et al 2018, we hypothesized that TG2 binds with transcription factors such as Zbtb7a to influence chromatin accessibility in astrocytes. In line with this hypothesis, VA4 significantly decreases TG2 binding to Zbtbt7a.…”

Section: Discussionmentioning

confidence: 99%

“…2008, Gundemir et al . 2013, Kim et al 2021, McConoughey et al . 2010, Monteagudo et al 2018, Rossin et al 2023), and Zbtb7a for regulating chromatin accessibility (Pittol et al 2018, Monteagudo et al 2018), we hypothesized that TG2 binds with transcription factors such as Zbtb7a to influence chromatin accessibility in astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Stabilizing transglutaminase 2 in the open conformation results in reactive astrocytes being more neurosupportive

Emerson,

Delgado,

Hong

et al. 2024

Preprint

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Astrocytes play critical roles in supporting structural and metabolic homeostasis in the central nervous system (CNS). Inflammatory conditions bring about a range of poorly understood, heterogeneous, reactive phenotypes in astrocytes. Finding ways to manipulate the phenotype of reactive astrocytes, and leveraging a pro-recovery phenotype, holds promise in treating CNS injury. Previous studies have shown that the protein transglutaminase 2 (TG2) plays a significant role in determining the phenotype of reactive astrocytes. Recently it has been demonstrated that ablation of TG2 from astrocytes improves injury outcomes both in vitro and in vivo. Excitingly, in an in vivo mouse model, pharmacological inhibition of TG2 with the irreversible inhibitor VA4 phenocopies the neurosupportive effects of TG2 deletion in astrocytes. The focus of this study was to provide insights into the mechanisms by which TG2 deletion or inhibition of TG2 with VA4 result in a more neurosupportive astrocytic phenotype. Using a neuron-astrocyte co-culture model of neurite outgrowth, we show that VA4 treatment improves the ability of astrocytes to support neurite outgrowth on an injury-relevant matrix, further validating the ability of VA4 to phenocopy astrocytic TG2 deletion. VA4 treatment of neurons alone had no effect on neurite outgrowth. VA4 covalently binds to active site residues of TG2 that are exposed in its open conformation and are critical for its enzymatic function, and prevents TG2 from taking on a closed conformation, which interferes with its protein scaffolding function. To begin to understand how pharmacologically altering TG2s conformation affects its ability to regulate reactive astrocyte phenotypes, we assayed the impact of VA4 on TG2s interaction with Zbtb7a, a transcription factor that we have previously identified as a TG2 interactor, and whose functional outputs are significantly regulated by TG2. The results of these studies demonstrated that VA4 significantly decreases the interaction of TG2 and Zbtb7a. Further, previous findings indicate that TG2 may act as an epigenetic regulator, through its nuclear protein-protein interactions, to modulate gene expression. Since both TG2 and Zbtb7a interact with members of the Sin3a chromatin repressor complex, we assayed the effect of TG2 deletion and VA4 treatment on histone acetylation and found significantly greater acetylation with TG2 deletion or inhibition with VA4. Overall, this work points toward a possible epigenetic mechanism by which genetic deletion or acute inhibition of TG2 leads to enhanced astrocytic support of neurons.

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“…In fact, it has been shown that TG2 physically interacts with the BAF250a (also known as ARID1a) protein which is a key component of the SWI/SNF complex (cBAF). In this case, TG2 catalyzes the covalent incorporation of polyamines into BAF250a [ 30 ]. cBAF is a key ATP-dependent chromatin remodelling complex playing an important tumour suppressor role.…”

Section: The Epigenetic Tg2 Regulatory Facementioning

confidence: 99%

Type 2 transglutaminase in the nucleus: the new epigenetic face of a cytoplasmic enzyme

Rossin

Ciccosanti

D’Eletto

et al. 2023

Cell. Mol. Life Sci.

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One of the major mysteries in science is how it is possible to pack the cellular chromatin with a total length of over 1 m, into a small sphere with a diameter of 5 mm “the nucleus”, and even more difficult to envisage how to make it functional. Although we know that compaction is achieved through the histones, however, the DNA needs to be accessible to the transcription machinery and this is allowed thanks to a variety of very complex epigenetic mechanisms. Either DNA (methylation) or post-translational modifications of histone proteins (acetylation, methylation, ubiquitination and sumoylation) play a crucial role in chromatin remodelling and consequently on gene expression. Recently the serotonylation and dopaminylation of the histone 3, catalyzed by the Transglutaminase type 2 (TG2), has been reported. These novel post-translational modifications catalyzed by a predominantly cytoplasmic enzyme opens a new avenue for future investigations on the enzyme function itself and for the possibility that other biological amines, substrate of TG2, can influence the genome regulation under peculiar cellular conditions. In this review we analyzed the nuclear TG2’s biology by discussing both its post-translational modification of various transcription factors and the implications of its epigenetic new face. Finally, we will focus on the potential impact of these events in human diseases.

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Transglutaminase 2 mediates transcriptional regulation through BAF250a polyamination

Cited by 9 publications

References 37 publications

Deletion of transglutaminase 2 from astrocytes significantly improves their ability to promote neurite outgrowth on an inhibitory matrix

Deletion of transglutaminase 2 from astrocytes significantly improves their ability to promote neurite outgrowth on an inhibitory matrix

Stabilizing transglutaminase 2 in the open conformation results in reactive astrocytes being more neurosupportive

Type 2 transglutaminase in the nucleus: the new epigenetic face of a cytoplasmic enzyme

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