Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements

Ibarra, Ignacio L.; Ratnu, Vikram S.; Gordillo, Lucia; Hwang, In Kyeom; Mariani, Luca; Weinand, Kathryn; Hammarén, Henrik M.; Heck, Jennifer; Bulyk, Martha L.; Savitski, Mikhail M.; Zaugg, Judith B.; Noh, Kyung‐Min

doi:10.15252/msb.202110473

Cited by 16 publications

(10 citation statements)

References 112 publications

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“…In this regard, an important discovery that may contribute to explaining this phenomenon is that PGRN deficiency resulted in excessive NF-κB activation in microglia and elevated TNF-α signaling, subsequently leading to the hyperexcitability of medium spiny neurons in the NAc [66]. Furthermore, the action of BDNF is based on its involvement in synaptic plasticity via the enhancement of dendritic arborization, axonal growth, and neurotransmitter release [67]. Thus, the increased dendritic and synaptic plasticity in the NAc seems to be attributed to increased expression of BDNF occurring in PGRNKO mice.…”

Section: Discussionmentioning

confidence: 99%

Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors

Wang

Lai

Zhou

et al. 2022

J Neuroinflammation

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Background Neuroinflammation in the nucleus accumbens (NAc) is well known to influence the progression of depression. However, the molecular mechanisms triggering NAc neuroinflammation in depression have not been fully elucidated. Progranulin (PGRN) is a multifunctional growth factor that is linked to the innate immune response and inflammation, and PGRN plays a key role in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, the purpose of this study was to validate whether PGRN was involved in the NAc neuroinflammation-promoted depressive-like phenotype. Methods A NAc neuroinflammation-relevant depression-like model was established using wild-type (WT) and PGRN-knockout (KO) mice after NAc injection with lipopolysaccharide (LPS), and various behavioral tests related to cognition, social recognition, depression and anxiety were performed with WT and PGRNKO mice with or without NAc immune challenge. RT‒PCR, ELISA, western blotting and immunofluorescence staining were used to determine the expression and function of PGRN in the neuroinflammatory reaction in the NAc after LPS challenge. The morphology of neurons in the NAc from WT and PGRNKO mice under conditions of NAc neuroinflammation was analyzed using Golgi–Cox staining, followed by Sholl analyses. The potential signaling pathways involved in NAc neuroinflammation in PGRNKO mice were investigated by western blotting. Results Under normal conditions, PGRN deficiency induced FTD-like behaviors in mice and astrocyte activation in the NAc, promoted the release of the inflammatory cytokines interleukin (IL)-6 and IL-10 and increased dendritic complexity and synaptic protein BDNF levels in the NAc. However, NAc neuroinflammation enhanced PGRN expression, which was located in astrocytes and microglia within the NAc, and PGRN deficiency in mice alleviated NAc neuroinflammation-elicited depression-like behaviors, seemingly inhibiting astrocyte- and microglia-related inflammatory reactions and neuroplasticity complexity in the NAc via the p38 and nuclear factor of kappa (NF-κB) signaling pathways present in the NAc after neuroinflammation. Conclusions Our results suggest that PGRN exerts distinct function on different behaviors, showing protective roles in the FTD-like behavior and detrimental effects on the neuroinflammation-related depression-like behavior, resulting from mediating astrocyte and microglial functions from the NAc in different status.

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Section: Discussionmentioning

confidence: 99%

Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors

Wang

Lai

Zhou

et al. 2022

J Neuroinflammation

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“…Furthermore, the action of BDNF is based on its involvement in synaptic plasticity via the enhancement of dendritic arborization, axonal growth, and neurotransmitter release [57]. Thus, the increased dendritic and synaptic plasticity in the NAc seems to be attributed to increased expression of BDNF occurring in the NAc in PGRNKO mice.…”

Section: Discussionmentioning

confidence: 99%

Progranulin in the Nucleus Accumbens Contributes to Neuroinflammation-Induced Depression-Like Behavior in Mice

Wang

Lai

Zhou

et al. 2022

Preprint

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BackgroundNeuroin ammation in the nucleus accumbens (NAc) is well known to in uence the progression of depression. However, the molecular mechanisms triggering NAc neuroin ammation in depression have not been fully elucidated. Progranulin (PGRN) is a multifunctional growth factor that is linked to the innate immune response and in ammation, and PGRN plays a key role in neurodegenerative diseases.Here, the purpose of this study was to validate whether PGRN was involved in the NAc neuroin ammation-promoted depressive-like phenotype. MethodsA NAc neuroin ammation-relevant depression-like model was established using wild-type (WT) and PGRN knockout (KO) mice after NAc injection with lipopolysaccharide (LPS), and various behavioral tests related to cognition, social recognition, depression and anxiety were performed with WT and PGRNKO mice with or without NAc immune challenge. RT-PCR, ELISA, western blotting and immuno uorescence staining were used to determine the expression and function of PGRN in the neuroin ammatory reaction in the NAc after LPS challenge. The morphology of neurons in the NAc from WT and PGRNKO mice under conditions of NAc neuroin ammation was analyzed using Golgi-Cox staining, followed by Sholl analyses.The potential signaling pathways involved in NAc neuroin ammation in PGRNKO mice were investigated by western blotting. ResultsUnder normal conditions, PGRN de ciency induced frontotemoral dementia (FTD)-like behaviors in mice and astrocyte activation in the NAc, promoted the release of the in ammatory cytokines interleukin (IL)-6 and IL-10 and increased dendritic complexity and synaptic protein BDNF levels in the NAc. However, NAc neuroin ammation enhanced PGRN expression, which was located in astrocytes and microglia within the NAc, and PGRN de ciency in mice alleviated NAc neuroin ammation-elicited depression-like behaviors, seemingly inhibiting astrocyte-and microglia-related in ammatory reactions and neuroplasticity complexity in the NAc via the p38 and nuclear factor of kappa (NF-κB) signaling pathways present in the NAc after neuroin ammation. ConclusionsOur results suggest that PGRN seems to exert distinct effects on different behaviors, such as FTD-like behavior and depression-like behavior, resulting from mediating astrocyte and microglial functions from the NAc in different status.

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“…Narrow peaks were called using MACS2 with paired-end default parameters, and windows of 150 bp centered on the peak summits for the top 1000 peaks (sorted by ChIP enrichment score) were used as the foreground set. For each peak set, a genomic background matched for length, G/C content, CpG content, promoter overlap, and repeat content was generated using GENRE 61 applied to the mouse genome 96 . Foreground and background regions containing a given 6-mer were counted and the significance of enrichment was tested by Fisher’s Exact Test in R. Sex of the donor was not considered when curating available ChIP data; both samples (human donor retina and mouse embryonic fibroblast cell line NIH-3T3) were from male donors.…”

Section: Methodsmentioning

confidence: 99%

DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues

Kock,

Kimes,

Gisselbrecht

et al. 2024

Nat Commun

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Homeodomains (HDs) are the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) and are the TF structural class with the largest number of disease-associated mutations in the Human Gene Mutation Database (HGMD). Despite numerous structural studies and large-scale analyses of HD DNA binding specificity, HD-DNA recognition is still not fully understood. Here, we analyze 92 human HD mutants, including disease-associated variants and variants of uncertain significance (VUS), for their effects on DNA binding activity. Many of the variants alter DNA binding affinity and/or specificity. Detailed biochemical analysis and structural modeling identifies 14 previously unknown specificity-determining positions, 5 of which do not contact DNA. The same missense substitution at analogous positions within different HDs often exhibits different effects on DNA binding activity. Variant effect prediction tools perform moderately well in distinguishing variants with altered DNA binding affinity, but poorly in identifying those with altered binding specificity. Our results highlight the need for biochemical assays of TF coding variants and prioritize dozens of variants for further investigations into their pathogenicity and the development of clinical diagnostics and precision therapies.

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Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements

Cited by 16 publications

References 112 publications

Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors

Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors

Progranulin in the Nucleus Accumbens Contributes to Neuroinflammation-Induced Depression-Like Behavior in Mice

DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues

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