Chromatin organizer SATB1 and Wnt transducer β-catenin form a complex and regulate expression of GATA3 and TH2 cytokines in Wnt-dependent manner and orchestrate TH2 lineage commitment.
SATB1 regulates gene expression by acting as a "docking site" for several chromatin remodeling enzymes and also by recruiting corepressors (HDACs) or coactivators (HATs) directly to promoters. However, how these contrasting effectors act at the level of SATB1 is not clear. We show here that phosphorylation by PKC acts as a switch to determine whether SATB1 interacts with HDAC1 or PCAF. Phosphorylation and dephosphorylation of SATB1 exerted opposing effects on MAR-linked reporter activity in vivo. SATB1 interacted with both CBP/p300 and PCAF HATs; however, these interactions resulted in the acetylation of the PDZ-like domain of SATB1 by PCAF but not by CBP/p300 and resulted in loss of its DNA binding activity. Using the T cell activation model, we provide mechanistic insights into how IL-2 transcription is reciprocally governed by the phosphorylation status of SATB1 and propose that a similar mechanism may dictate the ability of SATB1 to function as a global regulator.
SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug screening system and identified a small molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-Damage Response that are critical for SARS-CoV-2 infection. A drug-protein interaction based secondary screen confirmed compounds such as the ATR kinase inhibitor berzosertib and torin2 with anti SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and MERS-CoV as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.
The function of the subnuclear structure the promyelocytic leukaemia (PML) body is unclear largely because of the functional heterogeneity of its constituents. Here, we provide the evidence for a direct link between PML, higher-order chromatin organization and gene regulation. We show that PML physically and functionally interacts with the matrix attachment region (MAR)-binding protein, special AT-rich sequence binding protein 1 (SATB1) to organize the major histocompatibility complex (MHC) class I locus into distinct higher-order chromatin-loop structures. Interferon gamma (IFNgamma) treatment and silencing of either SATB1 or PML dynamically alter chromatin architecture, thus affecting the expression profile of a subset of MHC class I genes. Our studies identify PML and SATB1 as a regulatory complex that governs transcription by orchestrating dynamic chromatin-loop architecture.
Special AT-rich binding protein 1 (SATB1) acts as a global regulator of gene expression by recruiting various corepressor or coactivator complexes, thereby establishing a unique chromatin structure at its genomic targets in a context-dependent manner. Although SATB1 acts predominantly as a repressor via recruitment of histone deacetylase 1 (HDAC1) complexes, the precise mechanism of global repression is not clear. Here we report that SATB1 and C-terminal binding protein 1 (CtBP1) form a repressor complex in vivo. The interaction occurs via the CtBP1 interaction consensus motif PVPLS within the PDZ-like domain of SATB1. The acetylation of SATB1 upon LiCl and ionomycin treatments disrupts its association with CtBP1, resulting in enhanced target gene expression. Chromatin immunoprecipitation analysis indicated that the occupancy of CtBP1 and HDAC1 is gradually decreased and the occupancy of PCAF is elevated at the SATB1 binding sites within the human interleukin-2 and mouse c-Myc promoters. Moreover, gene expression profiling studies using cells in which expression of SATB1 and CtBP1 was silenced indicated commonly targeted genes that may be coordinately repressed by the SATB1-CtBP1 complex. Collectively, these results provide a mechanistic insight into the role of SATB1-CtBP1 interaction in the repression and derepression of SATB1 target genes during Wnt signaling in T cells.The T-cell-enriched transcription factor special AT-rich binding protein 1 (SATB1) regulates the spatiotemporal expression of a large number of genes involved in T-cell development (1). SATB1 participates in the maintenance of chromatin architecture in a cell-type-specific manner by organizing higher-order chromatin loops into distinct domains via periodic anchoring of non-base-pairing regions to the nuclear matrix (9, 10, 25). In primary thymocytes, SATB1 exhibits a cagelike network distribution circumscribing heterochromatin domains and regulates distant genes in a coordinated manner (10). Implications of SATB1 domains in its functional regulation impart unique properties to this chromatin organizer. The C-terminal homeodomain (HD) acts in concert with the Cut repeat-containing domain (CD) and directs high-affinity binding of SATB1 to its targets in a sequence-specific manner (35). The N-terminal PDZ-like domain aids in the formation of a homodimer that is essential for the DNA binding activity of SATB1 (15,35). The N-terminal region harboring the PDZlike domain is a putative interface for its interaction with various cellular and viral proteins (25-27). SATB1 regulates gene expression in two distinct modes. Primary regulation is by specific binding of SATB1 to promoters and upstream regions, thereby directly influencing the promoter activity. SATB1 is known to directly regulate a number of genes, including those encoding globin, interleukin-2 (IL-2), and IL-2 receptor ␣ (IL-2R␣), by recruiting either CBP (48) or histone deacetylase 1 (HDAC1) (26,27). Secondly, context-specific regulation of SATB1 stems from its unique ability to bind to mat...
To better understand DNA recognition and transcription activity by SATB1, the T-lineage-enriched chromatin organizer and transcription factor, we have determined its optimal DNA-binding sequence by random oligonucleotide selection. The consensus SATB1-binding sequence (CSBS) comprises a palindromic sequence in which two identical AT-rich half-sites are arranged as inverted repeats flanking a central cytosine or guanine. Strikingly, the CSBS half-site is identical to the conserved element ‘TAATA’ bound by the known homeodomains (HDs). Furthermore, we show that the high-affinity binding of SATB1 to DNA is dimerization-dependent and the HD also binds in similar fashion. Binding studies using HD-lacking SATB1 and binding target with increased spacer between the two half-sites led us to propose a model for SATB1–DNA complex in which the HDs bind in an antiparallel fashion to the palindromic consensus element via minor groove, bridged by the PDZ-like dimerization domain. CSBS-driven in vivo reporter analysis indicated that SATB1 acts as a repressor upon binding to the CSBS and most of its derivatives and the extent of repression is proportional to SATB1's binding affinity to these sequences. These studies provide mechanistic insights into the mode of DNA binding and its effect on the regulation of transcription by SATB1.
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