Biology subjects

Qiu, R.

Publications and source records attributed to Qiu, R..

36 records · Page 2Linked to original sources

bioRxiv2025

Tropomyosin 1 promotes platelet adhesion and clot contraction separate from its roles in developmental hematopoiesis

Genome-wide associations studies (GWAS) have linked the Tropomyosin 1 (Tpm1) gene locus to quantitative blood trait variation, but related mechanisms are unclear. Tpm1 encodes an actin-binding protein that stabilizes actin filaments and influences cell adhesion, signaling, and actomyosin contractility. Murine Tpm1 deficiency enhances embryonic hemogenic endothelial cell specification, but it was unclear if these effects extended to postnatal hematopoiesis. We used Cdh5Cre or VavCre models to conditionally ablate Tpm1 in endothelium or hematopoietic cells. Both models produced knockout mice in normal Mendelian ratios with complete Tpm1 ablation in postnatal blood. Endothelial Tpm1 deletion increased hemogenic endothelial cell specification, but did not change hematopoietic progenitor cell production nor adult blood counts. This suggested separate roles for Tpm1 in the embryonic and adult blood systems. GWAS suggested genetic architecture specifically linking decreased TPM1 expression to increased platelet count. We examined platelet lifespan and function to explain these findings. Tpm1KO increased platelet lifespan and diminished adhesion to fibronectin and fibrinogen. Decreased platelet clearance could explain increased platelet count in GWAS. Platelet fibrin binding is necessary for blood clot contraction, which reduces vascular occlusion following initial hemostasis. Tpm1KO reduced clot contraction and enhanced clot formation with worsened vascular occlusion in a ferric chloride-induced stroke model. These findings reveal a new role for Tpm1 in platelet function, offering insight into how cytoskeletal regulation impacts human platelet traits and pointing to novel targets to modify stroke risk and thrombotic disease.

cell biology↗

bioRxiv2025

Multimodal analysis of in vitro hematopoiesis reveals blood cell-specific genetic impacts on complex disease traits

In vitro hematopoiesis systems can be used to define mechanisms for blood cell formation and function, produce cell therapeutics, and model blood cell contributions to systemic disease. Hematopoietic progenitor cell (HPC) production remains inefficient, precluded by knowledge gaps related to specification and morphogenesis of specialized hemogenic endothelial cells, which undergo an endothelial-to-hematopoietic transition (EHT) to form HPCs. We elected to define changes in gene expression and chromatin organization during HPC formation to reveal regulatory mechanisms. Using paired single cell RNA/ATAC sequencing together with Hi-C, we profiled cells before and after EHT. Pathway analysis and pseudotime inferences confirmed a continuum of stromal and endothelial cells undergoing development into HE cells and lineage-based HPCs in vitro. In these cell types, we characterize cis-regulatory elements and transcriptional regulatory activities that facilitate EHT and HPC homeostasis, including for SNAI1, SOX17, TGF{beta}, STAT4, as well as for GFI1b and KLF1 in megakaryocyte- and erythroid-biased progenitors, respectively. We then leveraged our insights into chromatin organization among in vitro-derived cells to assess enrichments corresponding to human trait variation reported in human genome wide association studies. HPCs revealed locus enrichment for quantitative blood traits and autoimmune disease predisposition, which were particularly enriched in myeloid- and lymphoid-biased populations. Stromal and endothelial cells from our in vitro cultures were specifically enriched for accessible chromatin at blood pressure loci. Our findings reveal genes and mechanisms governing in vitro hematopoietic development and blood cell-related disease pathology.

genetics↗

bioRxiv2025

Multiple weak brakes act in concert to regulate STIM1 and control store-operated calcium entry

The ER Ca2+ sensor STIM1 evokes store-operated Ca2+ entry through the interaction of its cytosolic CRAC activation domain (CAD) with the plasma membrane Ca2+ channel Orai1 following ER Ca2+ depletion. To avoid pathophysiological effects, STIM1 must respond precisely and reversibly to changes in ER Ca2+ content while maintaining a low basal activity under resting, ER-replete conditions. Here we combine single-molecule FRET measurements of full-length dimeric STIM1 in lipid membranes with an AlphaFold2 structural model to describe the structure and regulation of the resting state. We show that STIM1 activity is controlled by the combined operation of four relatively weak restraints, or brakes. The Ca2+-bound EF-SAM luminal domain acts as a steric restraint to inhibit spontaneous activity. In the cytosolic region, the domain-swapped interaction and alignment of CC11 with CC3 of CAD positions the apex of CAD next to the ER membrane, where electrostatic lipid-protein interactions further stabilize the inactive conformation. A fourth brake is created by hydrophobic and electrostatic interactions of the two CC12/3 domains attached to the base of CAD. Disruption of any one of these brakes leads to STIM1 activation, showing that the concerted action of these relatively weak restraints is required to prevent spontaneous activity in resting cells with full ER Ca2+ stores, while enabling reversible activation in response to changes in store content.

biophysics↗

bioRxiv2025

Sludge liquefaction and stratification enable ultra-high digestion rate and resource recovery for waste activated sludge treatment

Most of the energy, nitrogen/N and phosphorus/P entering wastewater treatment plants (WWTPs) accumulates in waste activated sludge (WAS). While these resources are theoretically recoverable through anaerobic digestion (AD), conventional sludge AD faces long-standing challenges of low organic loading rate and limited N/P recovery. Here, building on an innovative sludge liquefaction and stratification technique, we present a novel process entitled SPREAD that boasts 10 times higher organic loading rates and recovers 5 folds of N/P resources, relative to conventional sludge AD. We develop an anaerobic digestion database (ADDB) for multi-omics analyses of digestion microbiomes, and pinpoint the mechanism underlying the exceptionally high organic loading rate and remarkable N/P recovery in SPREAD. Importantly, we identify a negative correlation between the Gibbs free energy ({Delta}G) and the relative abundance of methanogens, enabling identification of bottleneck steps for stimulation and augmentation of methanogenic digestion. Our study provides a game-changing technology for the treatment and resource recovery from WAS and opens a new avenue for sustainable management and carbon/energy-neutrality of WWTPs.

bioengineering↗

bioRxiv2024

Glutaredoxin 3 (GLRX3) confers a fusion oncogene-dependent vulnerability to Ewing sarcoma

Ewing sarcoma (EwS) is a highly aggressive bone and soft-tissue associated cancer for which there are no effective targeted therapeutics available. Genetically, EwS is driven by aberrantly active EWSR1::ETS fusion transcription factors, most commonly EWSR1::FLI1. Despite their unique expression in EwS, all attempts to effectively target these fusion oncoproteins clinically were not yet successful, wherefore alternative targets are required. Here, we functionally characterize the evolutionarily conserved oxidative stress regulator glutaredoxin 3 (GLRX3) as a EwS-specific and EWSR1::FLI1-dependent vulnerability. Through integration of transcriptome-profiling, conditional drug screens in 3D cultures, and functional experiments, we discover that GLRX3 promotes EwS growth in vitro and in vivo, and that it has a key role in mitigation of oxidative stress and maintenance of iron homeostasis. These GLRX3 functions can be exploited in both GLRX3-high and -low expressing EwS cells by targeted therapeutics including CDK4/6 inhibitors and inducers of apoptotic and ferroptotic cell death. Collectively, our results exemplify how the interplay of an evolutionarily conserved oxidative stress regulator with a dominant oncogene can promote malignancy but provide opportunities for predictive diagnostics and personalized therapy.

cancer biology↗

bioRxiv2024

VezA/vezatin facilitates proper assembly of the dynactin complex in vivo

Cytoplasmic dynein-mediated intracellular transport needs the multi-component dynactin complex for cargo binding and motor activation. However, cellular factors involved in dynactin assembly remain unexplored. Here we found in Aspergillus nidulans that the vezatin homolog VezA is important for dynactin assembly. VezA affects the microtubule plus-end accumulation of dynein before cargo binding and cargo adapter-mediated dynein activation, two processes that both need dynactin. The dynactin complex contains multiple components including an Arp1 (actin-related protein 1) mini-filament associated with a pointed-end sub-complex. VezA physically interacts with dynactin either directly or indirectly via the Arp1 mini-filament and its pointed-end sub-complex. Loss of VezA causes a defect in dynactin integrity, most likely by affecting the connection between the Arp1 mini-filament and its pointed-end sub-complex. Using various dynactin mutants, we further revealed that assembly of the dynactin complex must be highly coordinated. Together, these results shed important new light on dynactin assembly in vivo.

cell biology↗

bioRxiv2023

RBM39 shapes innate immunity through transcriptional and splicing control of IRF3 and other key factors

RNA-binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell metabolism, and development. Here, we performed a genome-wide CRISPR/Cas9 screen in two liver-derived cell lines and identified RBM39 as a regulator of cell intrinsic innate immune responses. The knockdown of RBM39 or the treatment with Indisulam, an aryl sulfonamide drug targeting RBM39 for proteasomal degradation, strongly reduced the induction of interferon-stimulated genes (ISGs) in response to double-stranded RNA (dsRNA) or viral infections upon sensing by toll-like receptor 3 (TLR3) or cytosolic RIG-I-like receptors. RNA sequencing (seq) and mass spectrometry identified that transcription and/or splicing of the key pathway components IRF3, RIG-I, and MDA5 were affected by RBM39 depletion. RBM39 knockdown further restrained type I and type III IFN pathways, by reducing expression of the type I IFN receptor subunit interferon alpha and beta receptor subunit 2 (IFNAR2), type III IFN receptor subunit interleukin 10 receptor subunit beta (IL-10RB) and transcription factor signal transducer and activator of transcription (STAT) 1 and 2. RBM39 overall orchestrates innate immunity by regulating basal expression of key factors of the interferon response via transcription and/or alternative splicing. SignificanceThe function of RBM39 in tumorigenesis has been investigated intensively in the last decade, but its immunological role is still largely unknown. In our study, we identified RBM39 as a regulatory factor of cell intrinsic signaling via a CRISPR/Cas9 screen. Depletion of RBM39 impairs TLR3, RIG-I/MDA5, and IFN pathways, and thus attenuates innate immune responses. Our omics analysis revealed that RBM39 governs the basal expression of several key factors within these pathways, such as RNA sensors RIG-I and MDA5, type I/III receptors, transcription factors IRF3, STAT1 and STAT2, via its transcriptional and splicing function. Therefore, RBM39 might be a therapeutic target to modulate innate immunity, e.g. in the context of autoimmune disorders.

immunology↗

bioRxiv2023

Aspergillus SUMOylation mutants have normal dynein function but exhibit chromatin bridges

AbstractFunctions of protein SUMOylation remain incompletely understood in different cell types. The budding yeast SUMOylation machinery interacts with LIS1, a protein critical for dynein activation, but dynein-pathway components were not identified as SUMO-targets in the filamentous fungus Aspergillus nidulans. Via A. nidulans forward genetics, here we identified ubaBQ247*, a loss-of-function mutation in a SUMO-activation enzyme UbaB. Colonies of the ubaBQ247*, {Delta}ubaB and {Delta}sumO mutants looked similar and less healthy than the wild-type colony. In these mutants, about 10% of nuclei are connected by abnormal chromatin bridges, indicating the importance of SUMOylation in the completion of chromosome segregation. Nuclei connected by chromatin bridges are mostly in interphase, suggesting that these bridges do not prevent cell-cycle progression. UbaB-GFP localizes to interphase nuclei just like the previously studied SumO-GFP, but the nuclear signals disappear during mitosis when the nuclear pores are partially open, and the signals reappear after mitosis. The nuclear localization is consistent with many SUMO-targets being nuclear proteins, for example, topoisomerase II whose SUMOylation defect gives rise to chromatin bridges in mammalian cells. Unlike in mammalian cells, however, loss of SUMOylation in A. nidulans does not apparently affect the metaphase-to-anaphase transition, further highlighting differences in the requirements of SUMOylation in different cell types. Finally, loss of UbaB or SumO does not affect dynein-and LIS1-mediated early-endosome transport, indicating that SUMOylation is unnecessary for dynein or LIS1 function in A. nidulans.

cell biology↗

bioRxiv2022

Genetically-Encoded Discovery of Perfluoroaryl-Macrocycles that Bind to Albumin and Exhibit Extended Circulation in-vivo

In this paper, we report selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine SNAr chemistry. Modification of phage-displayed libraries SXCXnC-phage, n=3-5, where X is any amino acid except for cysteine by decafluoro-diphenylsulfone (DFS), yields genetically-encoded library of octafluoro-diphen-ylsulfone-crosslinked macrocycles (OFS-SXCXnC-phage). Selection from these libraries using albumin as a bait identified a family of significantly enriched perfluoroaryl-macrocycles. Synthesis of perfluoroaryl-macrocycles predicted by phage display and testing their binding properties by 19F NMR and fluorescent polarization identified OFS-macrocycle with SICRFFC sequence as the most potent albumin binder. We observed that OFS-macrocycles slowly react with biological nucleophiles such as glutathione. Replacing decafluoro-diphenylsulfone by nearly isosteric pentafluorophenyl sulfide yielded perfluorophenylsulfide (PFS)-crosslinked macrocycles devoid of undesired reactivity. The augmented lead PFS-macrocycle with SICRFFC sequence exhibited KD = 4-6 M towards human serum albumin and similar affinities towards rat and mouse albumins. When injected in mouse, the PFS-SICRFFCGGG compound was significantly retained in circulation in vivo when compared to control PFS-macrocyclic peptide. The perfluoroaryl-macrocycles with SICRFFC motif are the smallest known peptide macrocycle with significant affinity for human albumin and they are a productive starting point for future development of compact macrocycles with predictable circulation half-life in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/504611v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@cd54d2org.highwire.dtl.DTLVardef@7bd9aborg.highwire.dtl.DTLVardef@10f7515org.highwire.dtl.DTLVardef@1cfc49a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Kinesin-1 undergoes autoinhibition but its functional significance has been unclear. Kinesin-1 transports multiple cargoes including cytoplasmic dynein to the microtubule plus ends. From a genetic screen for Aspergills mutants defective in dynein-mediated early endosome transport, we identified a kinesin-1 mutation kinAK895* that disrupts kinesin-1 autoinhibition. Consistent with kinAK895* making kinesin-1 constitutively active, the mutant proteins accumulate abnormally near the microtubule plus ends. Unexpectedly, our genetic data show that kinesin-1 autoinhibition is unnecessary for transporting its cargoes such as secretory vesicles. Dynein accumulates normally at the microtubule plus ends in the kinAK895* mutant. However, the frequency but not the speed of dynein-mediated early endosome transport is significantly decreased, indicating that kinesin-1 autoinhibition facilitates dynein to initiate its cargo transport. Furthermore, kinesin-1 autoinhibition promotes dynein cargo initiation in a way mechanistically distinct from LIS1-promoted dynein switching from its autoinhibited form. Thus, while dynein activation involves dynactin, cargo adapter and LIS1, this study adds kinesin-1 autoinhibition as a new regulatory factor in vivo.

cell biology↗

bioRxiv2021

Dynein activation in vivo is regulated by the nucleotide states of its AAA3 domain

Cytoplasmic dynein is activated by dynactin and cargo adapters in vitro, and the activation also needs LIS1 (Lissencephaly 1) in vivo. How this process is regulated remains unclear. Here we found in Aspergillus nidulans that a dynein AAA4 arginine-finger mutation bypasses the requirement of LIS1 for dynein activation driven by the early endosomal adapter HookA. As the AAA4 arginine-finger is implicated in AAA3 ATP hydrolysis, we examined AAA3 mutants defective in ATP binding and hydrolysis respectively. Astonishingly, blocking AAA3 ATP hydrolysis allows dynein activation by dynactin in the absence of LIS1 or HookA. As a consequence, dynein accumulates at microtubule minus ends while early endosomes stay near the plus ends. On the other hand, blocking AAA3 ATP binding abnormally prevents LIS1 from being dissociated from dynein upon motor activation. Thus, the AAA3 ATPase cycle regulates the coordination between dynein activation and cargo binding as well as the dynamic dynein-LIS1 interaction.

cell biology↗

bioRxiv2020

Conformational dynamics of auto-inhibition in the ER calcium sensor STIM1

The dimeric ER Ca2+ sensor STIM1 controls store-operated Ca2+ entry (SOCE) through the regulated binding of its CRAC activation domain (CAD) to Orai channels in the plasma membrane. In resting cells, the STIM1 CC1 domain interacts with CAD to suppress SOCE, but the structural basis of this interaction is unclear. Using single-molecule Forster resonance energy transfer (smFRET) and protein crosslinking approaches, we show that CC1 interacts dynamically with CAD in a domain-swapped configuration with an orientation predicted to sequester its Orai- binding region adjacent to the ER membrane. Following ER Ca2+ depletion and release from CAD, cysteine crosslinking indicates that the two CC1 domains become closely paired along their entire length in the active Orai-bound state. These findings provide a structural basis for the dual roles of CC1: sequestering CAD to suppress SOCE in resting cells and propelling it towards the plasma membrane to activate Orai and SOCE after store depletion.

biophysics↗

bioRxiv2020

Single-cell landscape of nuclear configuration and gene expression during stem cell differentiation and X inactivation

Mammalian development is associated with extensive changes in gene expression, chromatin accessibility, and nuclear structure. Here, we follow such changes associated with mouse embryonic stem cell differentiation and X inactivation by integrating, for the first time, allele-specific data obtained by high-throughput single-cell RNA-seq, ATAC-seq, and Hi-C. In differentiated cells, contact decay profiles, which clearly distinguish the active and inactive X chromosomes, reveal loss of the inactive X-specific structure at mitosis followed by a rapid reappearance, suggesting a bookkeeping mechanism. In differentiating embryonic stem cells, changes in contact decay profiles are detected in parallel on both the X chromosomes and autosomes, suggesting profound simultaneous reorganization. The onset of the inactive X-specific structure in single cells is notably delayed relative to that of gene silencing, consistent with the idea that chromatin compaction is a late event of X inactivation. Novel computational approaches to effectively align single-cell gene expression, chromatin accessibility, and 3D chromosome structure reveal that long-range structural changes to chromosomes appear as discrete events, unlike progressive changes in gene expression and chromatin accessibility.

genomics↗

bioRxiv2019

Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo

Deficiency of the LIS1 protein causes lissencephaly, a brain developmental disorder. Although LIS1 binds the microtubule motor cytoplasmic dynein and has been linked to dynein function in many experimental systems, its mechanism of action remains unclear. Here we revealed the function of LIS1 in cargo-adapter-mediated dynein activation in the model organism Aspergillus nidulans. Specifically, we found that overexpressed cargo adapter HookA (Hook in A. nidulans) missing its cargo-binding domain ({Delta}C-HookA) causes dynein and its regulator dynactin to relocate from the microtubule plus ends to the minus ends, and this dramatic relocation requires LIS1 and its binding protein NudE. Astonishingly, the requirement for LIS1 or NudE can be bypassed to a significant extent by specific mutations that open the auto-inhibited \"phi-dynein\" in which the motor domains of the dynein dimer are held close together. Our results suggest a novel mechanism of LIS1 action: it promotes the switch of dynein from the auto-inhibited state to an open state to facilitate dynein activation.\n\nSummaryThis study reveals the role of Lissencephaly 1 (LIS1) in cargo-adapter-mediated dynein activation. Furthermore, it discovers a novel mechanism of LIS1 action involving a switch of dynein from an auto-inhibited state to an active state.

cell biology↗

bioRxiv2019

NETosis proceeds by cytoskeleton and endomembrane disassembly and PAD4-mediated chromatin de-condensation and nuclear envelope rupture

Neutrophil extracellular traps (NETs) are web-like DNA structures decorated with histones and cytotoxic proteins that are released by activated neutrophils to trap and neutralize pathogens during the innate immune response, but also form in and exacerbate sterile inflammation. Peptidylarginine deiminase 4 (PAD4) citrullinates histones and is required for NET formation (NETosis) in mouse neutrophils. While the in vivo impact of NETs is accumulating, the cellular events driving NETosis and the role of PAD4 in these events are unclear. We performed high resolution time-lapse microscopy of mouse and human neutrophils (PMN) and differentiated HL-60 neutrophil-like cells (dHL-60) labelled with fluorescent markers of organelles and stimulated with ionomycin or lipopolysaccharides to induce NETosis. Upon stimulation, cells exhibited rapid disassembly of the actin cytoskeleton, followed by shedding of plasma membrane microvesicles, disassembly and remodeling of the microtubule and vimentin cytoskeletons, ER vesiculation, chromatin de-condensation and nuclear rounding, progressive plasma membrane and nuclear envelope (NE) permeabilization, nuclear lamin meshwork and then NE rupture to release DNA into the cytoplasm, and finally plasma membrane rupture and discharge of extracellular DNA. Inhibition of actin disassembly blocked NET release. Mouse and dHL-60 cells bearing genetic alteration of PAD4 showed that chromatin de-condensation, lamin meshwork and NE rupture and extracellular DNA release required the enzymatic and nuclear localization activities of PAD4. Thus, NETosis proceeds by a step-wise sequence of cellular events culminating in the PAD4-mediated expulsion of DNA.\n\nSignificance StatementNeutrophils are white blood cells specialized as the first line of host defense in the immune system. One way they protect organisms is through NETosis, in which they expel their DNA to form a web-like trap that ensnares pathogens and promotes clotting. However, NETs also mediate sterile inflammation, causing damage to the body. We used high-resolution live-cell microscopy to perform the first systematic characterization of the timing of dynamic cellular events leading to NETosis in human and mouse neutrophils and a neutrophil-like cell line. We discovered that NETosis proceeds by a step-wise sequence of cellular events that is conserved across species, and requires the activity of the PAD4 enzyme for DNA to be released from the nucleus and cell membrane.

immunology↗

bioRxiv2019

Sci-Hi-C: a single-cell Hi-C method for mapping 3D genome organization in large number of single cells

The highly dynamic nature of chromosome conformation and three-dimensional (3D) genome organization leads to cell-to-cell variability in chromatin interactions within a cell population, even if the cells of the population appear to be functionally homogeneous. Hence, although Hi-C is a powerful tool for mapping 3D genome organization, this heterogeneity of chromosome higher order structure among individual cells limits the interpretive power of population based bulk Hi-C assays. Moreover, single-cell studies have the potential to enable the identification and characterization of rare cell populations or cell subtypes in a heterogeneous population. However, it may require surveying relatively large numbers of single cells to achieve statistically meaningful observations in single-cell studies. By applying combinatorial cellular indexing to chromosome conformation capture, we developed single-cell combinatorial indexed Hi-C (sci-Hi-C), a high throughput method that enables mapping chromatin interactomes in large number of single cells. We demonstrated the use of sci-Hi-C data to separate cells by karytoypic and cell-cycle state differences and to identify cellular variability in mammalian chromosomal conformation. Here, we provide a detailed description of method design and step-by-step working protocols for sci-Hi-C.

genomics↗

bioRxiv2019

Capturing cell type-specific chromatin structural patterns by applying topic modeling to single-cell Hi-C data

Single-cell Hi-C (scHi-C) interrogates genome-wide chromatin interaction in individual cells, allowing us to gain insights into 3D genome organization. However, the extremely sparse nature of scHi-C data poses a significant barrier to analysis, limiting our ability to tease out hidden biological information. In this work, we approach this problem by applying topic modeling to scHi-C data. Topic modeling is well-suited for discovering latent topics in a collection of discrete data. For our analysis, we generate twelve different single-cell combinatorial indexed Hi-C (sciHi-C) libraries from five human cell lines (GM12878, H1Esc, HFF, IMR90, and HAP1), consisting over 25,000 cells. We demonstrate that topic modeling is able to successfully capture cell type differences from sciHi-C data in the form of "chromatin topics." We further show enrichment of particular compartment structures associated with locus pairs in these topics.

genomics↗

bioRxiv2017

MicroRNA-21 Regulates Metabolic Adaptation of Pathogenic TH17 cells and Controls Autoimmune Inflammation

TH17 cells exhibit great heterogeneity and variable functional states in vivo. However, metabolic reprogramming of TH17 cells in vivo and its regulation during autoimmunity and host defence is unknown. Here we report that TH17 cells derived in vivo show discrete metabolic states. Metabolic states of TH17 cells in vivo were controlled at the epigenetic level, with conserved regulatory region of key metabolic regulators show distinct chromatin accessibility as demonstrated by chromatin landscape profiling. TGF-{beta}1 signaling was further shown to be crucial for remodeling of TH17 cell chromatin states, Ahr and miR-21 were identified as essential metabolic regulators for TH17 cells. Understanding metabolic reprogramming of TH17 cells in vivo may therefore provide more defined therapeutic intervention to TH17 cell mediated autoimmune diseases and insights into TH17 cell mediated host defence.

immunology↗