Charting the Multi-level Molecular Response to Palbociclib in ER-Positive Breast Cancer.

The addition of CDK4/6 inhibitors to endocrine therapy has significantly improved outcomes in HR+/HER2- breast cancer. However, variable patient responses and acquired resistance remain a clinical challenge. We therefore defined the comprehensive molecular response to palbociclib, the most clinically used CDK4/6 inhibitor.

Coordinated expression of retained introns and poison exons in renal cell carcinoma.

The regulation and impact of tumor-specific isoforms in cancer is challenging to understand, with unclear links between oncogenic signaling and mRNA processing and decay. Using transcriptomic analyses and experimental validation, we demonstrate that clear cell renal cell carcinoma (ccRCC) tumors exhibit coordinated intron retention (IR) and poison exon (PE) inclusion, generating transcripts targeted by nonsense-mediated decay (NMD). ccRCC tumors segregate into two subtypes based on IR: tumors with low IR levels and those with high IR levels, the latter associated with aggressive clinical features and poorer survival.

Contributions of Folded and Disordered Domains to RNA Binding by HNRNPR.

RNA binding proteins (RBPs) interact with and tightly regulate the fate of messenger RNAs but how RNA targets are recognized remains a challenging question. RBPs often contain multiple domains known to directly bind RNA, such as RNA recognition motifs (RRMs), as well as domains whose RNA binding capacity remains incompletely understood, low complexity domains (LCDs). Here, we dissect HNRNPR, an RBP with three RRMs and an arginine-glycine rich (RG-rich) LCD.

The role of the L421P mutation in Penicillin-Binding Protein 1 (PBP1) in the evolution of chromosomally mediated penicillin resistance in .

Unlabelled: encodes a mutated variant of penicillin-binding protein 1 (PBP1) and is a key resistance determinant that increases the penicillin MIC (MIC ) above the clinical breakpoint in . Despite the removal of penicillin from treatment guidelines for gonococcal infections in the 1980s, is present in nearly 50% of current isolates in the PubMLST database. Bioinformatic analysis indicates that is exclusive to isolates, whereas Leu-421 is 100% conserved in other species.

Repeat A coordinates an assembly of SR proteins to recruit SPEN and induce gene silencing.

The lncRNA silences gene expression by recruiting the protein SPEN through its 5'-proximal Repeat A domain. How Repeat A recruits SPEN, how SPEN enacts silencing, and why Repeat A is required for biogenesis in addition to silencing remain unclear. We find that sequences in Repeat A critical for SPEN recruitment, silencing, and biogenesis directly bind SR-rich splicing factors and not SPEN.

Snord67 promotes breast cancer metastasis by guiding U6 modification and modulating the splicing landscape.

Previously considered "housekeeping" genes, small nucleolar RNAs (snoRNAs) are increasingly understood to have wide-ranging functions in cancer, yet their role in metastasis has been less well studied. Here, we identify the snoRNA Snord67 as a regulator of lymph node (LN) metastasis in breast cancer. Snord67 expression is enriched in LN metastases in an immune-competent mouse model of female breast cancer.

Alternative splicing of the Snap23 microexon is regulated by MBNL, QKI, and RBFOX2 in a tissue-specific manner and is altered in striated muscle diseases.

The reprogramming of alternative splicing networks during development is a hallmark of tissue maturation and identity. Alternative splicing of microexons (small, genomic regions ≤ 51 nucleotides) functionally regulate protein-protein interactions in the brain and is altered in several neuronal diseases. However, little is known about the regulation and function of alternatively spliced microexons in striated muscle.

Dissecting RNA selectivity mediated by tandem RNA-binding domains.

RNA-protein interactions are pivotal to proper gene regulation. Many RNA-binding proteins possess multiple RNA-binding domains; however, how these domains interplay to select and regulate RNA targets remains poorly understood. Here, we investigate three multidomain proteins, Musashi-1, Musashi-2, and unkempt, which share a high degree of RNA specificity, a common feature across RNA-binding proteins.

Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers.

Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL).

Adverse outcomes in monochorionic twins with amniotic fluid abnormalities without TTTS: A Case-Control study.

Objective: Monochorionic diamniotic (MCDA) twins with amniotic fluid abnormalities that do not meet criteria for twin-twin transfusion syndrome (TTTS) concern physicians and families. This study aimed to describe the natural history of amniotic fluid abnormalities.

Methods: In this retrospective case-control study, TTTS screening ultrasounds and clinical records throughout all MCDA twin gestations were reviewed between 2018 and 2022 at a tertiary fetal care center.

Visualizing liquid-liquid phase transitions.

Liquid-liquid phase condensation governs a wide range of protein-protein and protein-RNA interactions in vivo and drives the formation of membrane-less compartments such as the nucleolus and stress granules. We have a broad overview of the importance of multivalency and protein disorder in driving liquid-liquid phase transitions. However, the large and complex nature of key proteins and RNA components involved in forming condensates such as stress granules has inhibited a detailed understanding of how condensates form and the structural interactions that take place within them.

Understanding species-specific and conserved RNA-protein interactions in vivo and in vitro.

While evolution is often considered from a DNA- and protein-centric view, RNA-based regulation can also impact gene expression and protein sequences. Here we examine interspecies differences in RNA-protein interactions using the conserved neuronal RNA-binding protein, Unkempt (UNK) as model. We find that roughly half of mRNAs bound in human are also bound in mouse.

Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation.

RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation.

Regulation of synapse density by Pumilio RNA-binding proteins.

The formation, stabilization, and elimination of synapses are tightly regulated during neural development and into adulthood. Pumilio RNA-binding proteins regulate the translation and localization of many synaptic mRNAs and are developmentally downregulated in the brain. We found that simultaneous downregulation of Pumilio 1 and 2 increases both excitatory and inhibitory synapse density in primary hippocampal neurons and promotes synapse maturation.

Regulation by the RNA-binding protein Unkempt at its effector interface.

How RNA-binding proteins (RBPs) convey regulatory instructions to the core effectors of RNA processing is unclear. Here, we document the existence and functions of a multivalent RBP-effector interface. We show that the effector interface of a conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of 'dual-purpose' peptide motifs that can contact two different surfaces of interacting proteins.

Protein G-quadruplex interactions and their effects on phase transitions and protein aggregation.

The SERF family of proteins were originally discovered for their ability to accelerate amyloid formation. Znf706 is an uncharacterized protein whose N-terminus is homologous to SERF proteins. We show here that human Znf706 can promote protein aggregation and amyloid formation.

Understanding species-specific and conserved RNA-protein interactions and .

While evolution is often considered from a DNA- and protein-centric view, RNA-based regulation can also impact gene expression and protein sequences. Here we examined interspecies differences in RNA-protein interactions using the conserved neuronal RNA binding protein, Unkempt (UNK) as model. We find that roughly half of mRNAs bound in human are also bound in mouse.

Nanoelectromechanical Control of Spin-Photon Interfaces in a Hybrid Quantum System on Chip.

Color centers (CCs) in nanostructured diamond are promising for optically linked quantum technologies. Scaling to useful applications motivates architectures meeting the following criteria: C1 individual optical addressing of spin qubits; C2 frequency tuning of spin-dependent optical transitions; C3 coherent spin control; C4 active photon routing; C5 scalable manufacturability; and C6 low on-chip power dissipation for cryogenic operations. Here, we introduce an architecture that simultaneously achieves C1-C6.

Synchronous micromechanically resonant programmable photonic circuits.

Programmable photonic integrated circuits (PICs) are emerging as powerful tools for control of light, with applications in quantum information processing, optical range finding, and artificial intelligence. Low-power implementations of these PICs involve micromechanical structures driven capacitively or piezoelectrically but are often limited in modulation bandwidth by mechanical resonances and high operating voltages. Here we introduce a synchronous, micromechanically resonant design architecture for programmable PICs and a proof-of-principle 1×8 photonic switch using piezoelectric optical phase shifters.

Protein G-quadruplex interactions and their effects on phase transitions and protein aggregation.

The SERF family of proteins were originally discovered for their ability to accelerate amyloid formation. Znf706 is an uncharacterized protein whose N-terminus is homologous to SERF proteins. We show here that human Znf706 can promote protein aggregation and amyloid formation.

SAFB associates with nascent RNAs and can promote gene expression in mouse embryonic stem cells.

Scaffold attachment factor B (SAFB) is a conserved RNA-binding protein that is essential for early mammalian development. However, the functions of SAFB in mouse embryonic stem cells (ESCs) have not been characterized. Using RNA immunoprecipitation followed by RNA-seq (RIP-seq), we examined the RNAs associated with SAFB in wild-type and SAFB/SAFB2 double-knockout ESCs.

Emerging roles for G-quadruplexes in proteostasis.

How nucleic acids interact with proteins, and how they affect protein folding, aggregation, and misfolding is a still-evolving area of research. Considerable effort is now focusing on a particular structure of RNA and DNA, G-quadruplexes, and their role in protein homeostasis and disease. In this state-of-the-art review, we track recent reports on how G-quadruplexes influence protein aggregation, proteolysis, phase separation, and protein misfolding diseases, and pose currently unanswered questions in the advance of this scientific field.

Multi-Omics Analysis of Multiple Glucose-Sensing Receptor Systems in Yeast.

The yeast has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here, we compare the two glucose receptor systems in .

Quantitative profiling of adaptation to cyclin E overproduction.

Cyclin E/CDK2 drives cell cycle progression from G1 to S phase. Despite the toxicity of cyclin E overproduction in mammalian cells, the cyclin E gene is overexpressed in some cancers. To further understand how cells can tolerate high cyclin E, we characterized non-transformed epithelial cells subjected to chronic cyclin E overproduction.

Alternative splicing regulation of membrane trafficking genes during myogenesis.

Alternative splicing transitions occur during organ development, and, in numerous diseases, splicing programs revert to fetal isoform expression. We previously found that extensive splicing changes occur during postnatal mouse heart development in genes encoding proteins involved in vesicle-mediated trafficking. However, the regulatory mechanisms of this splicing-trafficking network are unknown.