Single-Cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape.

Cell differentiation during organogenesis relies on precise epigenetic and transcriptional control. Disruptions to this regulation can result in developmental abnormalities and malignancies, yet the underlying mechanisms are not well understood. Wilms tumors, a type of embryonal tumor closely linked to disrupted organogenesis, harbor mutations in epigenetic regulators in 30-50% of cases. However, the role of these regulators in kidney development and pathogenesis remains unexplored. By integrating mouse modeling, histological characterizations, and single-cell transcriptomics and chromatin accessibility profiling, we show that a Wilms tumor-associated mutation in the chromatin reader protein ENL disrupts kidney development trajectory by rewiring the gene regulatory landscape. Specifically, the mutant ENL promotes the commitment of nephron progenitors while simultaneously restricting their differentiation by dysregulating key transcription factor regulons, particularly the HOX clusters. It also induces the emergence of abnormal progenitor cells that lose their chromatin identity associated with kidney specification. Furthermore, the mutant ENL might modulate stroma-nephron interactions via paracrine Wnt signaling. These multifaceted effects caused by the mutation result in severe developmental defects in the kidney and early postnatal mortality in mice. Notably, transient inhibition of the histone acetylation binding activity of mutant ENL with a small molecule displaces transcriptional condensates formed by mutant ENL from target genes, abolishes its gene activation function, and restores developmental defects in mice. This work provides new insights into how mutations in epigenetic regulators can alter the gene regulatory landscape to disrupt kidney developmental programs at single-cell resolution in vivo . It also offers a proof-of-concept for the use of epigenetics-targeted agents to rectify developmental defects.

RUNX1 C-terminal mutations impair blood cell differentiation by perturbing specific enhancer-promoter networks.

ABSTRACT: The transcription factor RUNX1 is a master regulator of hematopoiesis and is frequently mutated in myeloid malignancies. Mutations in its runt homology domain (RHD) frequently disrupt DNA binding and result in loss of RUNX1 function. However, it is not clearly understood how other RUNX1 mutations contribute to disease development. Here, we characterized RUNX1 mutations outside of the RHD. Our analysis of the patient data sets revealed that mutations within the C-terminus frequently occur in hematopoietic disorders. Remarkably, most of these mutations were nonsense or frameshift mutations and were predicted to be exempt from nonsense-mediated messenger RNA decay. Therefore, this class of mutation is projected to produce DNA-binding proteins that contribute to the pathogenesis in a distinct manner. To model this, we introduced the RUNX1R320∗ mutation into the endogenous gene locus and demonstrated the production of RUNX1R320∗ protein. Expression of RUNX1R320∗ resulted in the disruption of RUNX1 regulated processes such as megakaryocytic differentiation, through a transcriptional signature different from RUNX1 depletion. To understand the underlying mechanisms, we used Global RNA Interactions with DNA by deep sequencing (GRID-seq) to examine enhancer-promoter connections. We identified widespread alterations in the enhancer-promoter networks within RUNX1 mutant cells. Additionally, we uncovered enrichment of RUNX1R320∗ and FOXK2 binding at the MYC super enhancer locus, significantly upregulating MYC transcription and signaling pathways. Together, our study demonstrated that most RUNX1 mutations outside the DNA-binding domain are not subject to nonsense-mediated decay, producing protein products that act in concert with additional cofactors to dysregulate hematopoiesis through mechanisms distinct from those induced by RUNX1 depletion.

Coexistence of Dirac points and nodal chains in photonic metacrystal.

Gapless topological phases, i.e. topological semimetals, come in various forms such as Weyl/Dirac semimetals, nodal line/chain semimetals, and surface-node semimetals. However, the coexistence of two or more topological phases in a single system is still rare. Here, we propose the coexistence of Dirac points and nodal chain degeneracies in a judiciously designed photonic metacrystal. The designed metacrystal exhibits nodal line degeneracies lying in perpendicular planes, which are chained together at the Brillouin zone boundary. Interestingly, the Dirac points, which are protected by nonsymmorphic symmetries, are located right at the intersection points of nodal chains. The nontrivial Z2 topology of the Dirac points is revealed by the surface states. The Dirac points and nodal chains are located in a clean frequency range. Our results provide a platform for studying the connection between different topological phases.

Scalar topological photonic nested meta-crystals and skyrmion surface states in the light cone continuum.

Topological photonics is rapidly expanding. However, discovering three-dimensional topological electromagnetic systems can be more challenging than electronic systems for two reasons. First, the vectorial nature of electromagnetic waves results in complicated band dispersions, and simple tight-binding-type predictions usually fail. Second, topological electromagnetic surface modes inside the light cone have very low quality factors (Q factors). Here, we propose the concept of scalar topological photonics to address these challenges. Our approach is experimentally validated by employing a nested meta-crystal configuration using connected coaxial waveguides. They exhibit scalar-wave-like band dispersions, making the search for photonic topological phases an easier task. Their surface states have skyrmion-like electric field distributions, resulting in a whole, bright surface state band inside the light cone continuum. As such, the topological surface states in our three-dimensional nested crystals can be exposed to air, making such systems well-suited for practical applications.

Dirac-Weyl semimetal in photonic metacrystals.

Dirac-Weyl semimetal is a novel type of topological phase that features the coexistence of Dirac and Weyl points in momentum space. In this study, a photonic Dirac-Weyl semimetal is proposed by introducing screw rotation symmetries into a spatial inversion symmetry-lacking system. A realistic metacrystal structure is designed for experimental consideration. The screw rotation symmetries are crucial for the existence of Dirac points, whose Z2 topology is revealed by the (010) surface states. Meanwhile, two pairs of ideal Weyl points at the same frequency are protected by D2d point group symmetries. The Dirac points and Weyl points reside in a clean frequency interval. The proposed photonic Dirac-Weyl semimetal provides a versatile platform for exploring the interaction between Dirac and Weyl semimetals and exploiting possible photonic topological devices.

Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer.

Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism.

Malignancies in people living with HIV.

Almost 40 years have passed since the first case of what is known as AIDS was documented. In these 40 years, AIDS has always been a research challenge and hot spot. Researchers and scientists have made tremendous progress in basic and clinical research on HIV. In particular, the widespread use of antiretroviral therapy (ART) has made it less of a deadly disease today and more of a manageable one. In the post- ART era when ART can significantly improve the immunity of people living with HIV (PLWH) and extend their life, the incidence of non-AIDS-defined cancers is greatly increased. Factors related to immunosuppression do not seem to explain this problem sufficiently. This suggests that besides immunosuppression, there are other mechanisms that may also contribute to the increased incidence of cancer in PLWH. Here, we summarized and discussed four possible mechanisms for the increased incidence of cancers in PLWH: immunosuppression, oncogenic viral infection, chronic infection, inflammatory damage, and the direct impact of HIV.

Tumor Microenvironment Profiles Reveal Distinct Therapy-Oriented Proteogenomic Characteristics in Colorectal Cancer.

Advances in immunotherapy have made an unprecedented leap in treating colorectal cancer (CRC). However, more effective therapeutic regimes need a deeper understanding of molecular architectures for precise patient stratification and therapeutic improvement. We profiled patients receiving neoadjuvant chemotherapy alone or in combination with immunotherapy (PD-1 checkpoint inhibitor) using Digital Spatial Profiler (DSP), a high-plex spatial proteogenomic technology. Compartmentalization-based high-plex profiling of both proteins and mRNAs revealed pronounced immune infiltration at tumor regions associated with immunotherapy treatment. The protein and the corresponding mRNA levels within the same selected regions of those patient samples correlate, indicating an overall concordance between the transcriptional and translational levels. An elevated expression of PD-L1 at both protein and the mRNA levels was discovered in the tumor compartment of immunotherapy-treated patients compared with chemo-treated patients, indicating potential prognostic biomarkers are explorable in a spatial manner at the local tumor microenvironment (TME). An elevated expression of PD-L1 was verified by immunohistochemistry. Other compartment-specific biomarkers were also differentially expressed between the tumor and stromal regions, indicating a dynamic interplay that can potentiate novel biomarker discovery from the TME perspectives. Simultaneously, a high-plex spatial profiling of protein and mRNA in the tumor microenvironment of colorectal cancer was performed.

Intrinsic in-plane nodal chain and generalized quaternion charge protected nodal link in photonics.

Nodal lines are degeneracies formed by crossing bands in three-dimensional momentum space. Interestingly, these degenerate lines can chain together via touching points and manifest as nodal chains. These nodal chains are usually embedded in two orthogonal planes and protected by the corresponding mirror symmetries. Here, we propose and demonstrate an in-plane nodal chain in photonics, where all chained nodal lines coexist in a single mirror plane instead of two orthogonal ones. The chain point is stabilized by the intrinsic symmetry that is specific to electromagnetic waves at the Г point of zero frequency. By adding another mirror plane, we find a nodal ring that is constructed by two higher bands and links with the in-plane nodal chain. The nodal link in momentum space exhibits non-Abelian characteristics on a C2T - invariant plane, where admissible transitions of the nodal link structure are determined by generalized quaternion charges. Through near-field scanning measurements of bi-anisotropic metamaterials, we experimentally mapped out the in-plane nodal chain and nodal link in such systems.

Cellular and Immune Therapy for Treating HIV-1 Infection.

HIV-1 infection has caused a number of deaths worldwide and remains a global health concern. Combined antiretroviral therapy (cART) inhibits viral replication, prevents CD4+ T cell loss, and thus slows HIV disease progression. However, cART does not eradicate HIV-1. Infected individuals must remain on treatment for their entire lives and treatment interruption will result in viral rebound.

Observation of Non-Abelian Nodal Links in Photonics.

In crystals, two bands may cross each other and form degeneracies along a closed loop in the three-dimensional momentum space, which is called nodal line. Nodal line degeneracy can be designed to exhibit various configurations such as nodal rings, chains, links, and knots. Very recently, non-Abelian band topology was proposed in nodal link systems, where the nodal lines formed by consecutive pairs of bands exhibit interesting braiding structures and the underlying topological charges are described by quaternions. Here, we experimentally demonstrate non-Abelian nodal links in a biaxial hyperbolic metamaterial. The linked nodal lines threading through each other are formed by the crossings between three adjacent bands. Based on the non-Abelian charges, we further analyze various admissible nodal link configurations for the three-band system. On the interface between the metamaterial and air, surface bound states in the continuum are observed, which serves as the symmetry-enforced derivative of drumhead surface states from the linked nodal lines. Our work serves as a direct observation of the global topological structures of nodal links, and provides a platform for studying non-Abelian topological charge in the momentum space.

Spontaneous Emission and Resonant Scattering in Transition from Type I to Type II Photonic Weyl Systems.

Spontaneous emission and scattering behavior of an emitter or a resonant scatterer strongly depend on the density of states of the surrounding medium. It has been shown that the resonant scattering cross section (RSC) may diverge at the Weyl frequency of a type I Weyl system due to the diminishing density of states. Here we study the spontaneous emission (SE) and RSC in a photonic metacrystal across the critical transition between type I and type II Weyl systems. Theoretical results show that the SE rate of an emitter in a type I Weyl system diminishes to zero at the Weyl frequency. When the system is tuned towards the transition point between type I and type II Weyl point, the dip in the SE spectrum at the Weyl frequency becomes infinitely sharp. The dip vanishes at the critical transition, and transforms into a peak when the system changes into a type II Weyl system. We further show that the resonant scattering cross section also exhibits dramatically different spectral features across the transition. Our study demonstrates the ability to tune SE and RSC through altering the dispersion of the Weyl medium between type I and type II, which provides a fundamentally new route in manipulating light-matter interactions.

Observation of Hourglass Nodal Lines in Photonics.

Nodal line semimetals exhibiting line degeneracies in three-dimensional momentum space have been demonstrated recently. In general, the presence of nodal line semimetals is protected by special symmetries, such as mirror symmetry. However, these symmetries are usually necessary but not sufficient conditions, as nodal lines can be annihilated even without breaking them. Very recently, nodal line semimetal possessing an hourglass-shaped band structure emerges as a more robust candidate, where line degeneracies cannot be annihilated while preserving all underlying spatial symmetries. Here, for the first time, we experimentally demonstrate the presence of an hourglass nodal line (HNL) in photonic metacrystal at microwave frequency. We observe the HNL through near-field scanning of the spatial fields, followed by subsequent Fourier transformations. The observed photonic HNL resides in a clean and large frequency interval and is immune to symmetry preserving perturbation, which provides an ideal robust platform for photonic applications, such as anomalous quantum oscillation, spontaneous emission and resonant scattering.

Experimental observation of photonic nodal line degeneracies in metacrystals.

Nodal line semimetals (NLS) are three-dimensional (3D) crystals that support band crossings in the form of one-dimensional rings in the Brillouin zone. In the presence of spin-orbit coupling or lowered crystal symmetry, NLS may transform into Dirac semimetals, Weyl semimetals, or 3D topological insulators. In the photonics context, despite the realization of topological phases, such as Chern insulators, topological insulators, Weyl, and Dirac degeneracies, no experimental demonstration of photonic nodal lines (NLs) has been reported so far. Here, we experimentally demonstrate NL degeneracies in microwave cut-wire metacrystals with engineered negative bulk plasma dispersion. Both the bulk and surface states of the NL metamaterial are observed through spatial Fourier transformations of the scanned near-field distributions. Furthermore, we theoretically show that the NL degeneracy can transform into two Weyl points when gyroelectric materials are incorporated into the metacrystal design. Our findings may inspire further advances in topological photonics.

Three Dimensional Photonic Dirac Points in Metamaterials.

Topological semimetals, representing a new topological phase that lacks a full band gap in bulk states and exhibiting nontrivial topological orders, recently have been extended to photonic systems, predominantly in photonic crystals and to a lesser extent metamaterials. Photonic crystal realizations of Dirac degeneracies are protected by various space symmetries, where Bloch modes span the spin and orbital subspaces. Here, we theoretically show that Dirac points can also be realized in effective media through the intrinsic degrees of freedom in electromagnetism under electromagnetic duality. A pair of spin-polarized Fermi-arc-like surface states is observed at the interface between air and the Dirac metamaterials. Furthermore, eigenreflection fields show the decoupling process from a Dirac point to two Weyl points. We also find the topological correlation between a Dirac point and vortex or vector beams in classical photonics. The experimental feasibility of our scheme is demonstrated by designing a realistic metamaterial structure. The theoretical proposal of the photonic Dirac point lays the foundation for unveiling the connection between intrinsic physics and global topology in electromagnetism.