Goldberg Fellows

The vagus nerve contains specialized sensory neurons that monitor circulation and rapidly adjust heart rate and blood pressure. Although the roles of arterial baroreceptors in systemic physiology are well appreciated, the function of cardiac vagal receptors that detect changes in the heart remained poorly understood. In the Liberles lab, I use mouse genetics, in vivo physiology, nerve recording, and calcium imaging to identify distinct cardiac sensory neuron types and determine how they contribute to cardiovascular homeostasis.

In my recent postdoc work, I identified a small population of vagal PIEZO2-expressing mechanoreceptors in the heart that function as blood volume receptors. These neurons fire with every heartbeat, track changes in cardiac filling, and initiate a reflex that helps maintain circulatory stability. Disrupting this pathway abolishes heartbeat-coupled vagal activity, causes orthostatic hypotension during postural change, and compromises cardiovascular stability during trauma-induced blood loss.

My ongoing research seeks to identify additional sensory receptors in the heart, determine how cardiac sensory signals are represented in the brain, and understand how heart-to-brain pathways support physiological adaptation in health and disease. More broadly, I am interested in how neural circuits transform cardiovascular sensory information into autonomic responses that preserve homeostasis under stress.

Eukaryotic genomes are hierarchically organized in three-dimensional (3D) space to facilitate compaction and to regulate essential nuclear processes such as transcription, DNA replication, recombination, and DNA repair. Disruption of this 3D genome architecture has profound effects on gene regulation and is increasingly associated with developmental disorders, cancer, and other diseases. A key architectural regulator of genome organization is the CCCTC-binding factor (CTCF), which, in concert with the multi-subunit complex cohesin, folds the genome into chromatin loops that demarcate regulatory domains, mediate enhancer insulation, and enable long-range chromatin interactions critical for proper transcriptional control. Despite extensive genomic and biochemical studies, key mechanistic principles underlying CTCF-mediated genome folding remain incompletely understood, and direct structural information on how CTCF engages chromatinized DNA is still lacking. My ongoing research in the Farnung lab addresses these questions using biochemical, structural, and 3D genomic approaches. 

Stable gene silencing is essential for development and tissue specification, ensuring that cell-type–specific transcriptional programs are maintained while inappropriate lineage genes remain off. In eukaryotes, Polycomb complexes establish facultative heterochromatin to keep developmental genes stably repressed. Yet many Polycomb domains are transcribed, suggesting that transcription can be compatible with—and may even contribute to—silencing when nascent RNA is properly processed and cleared.

Recent work has identified the rixosome as a key effector of Polycomb target gene silencing in mammalian cells, but how rixosome-mediated nascent RNA decay preserves Polycomb heterochromatin remains unknown. With support from the Goldberg Fellowship, I will ask: which nascent RNAs are directly targeted by the rixosome at Polycomb-target genes, and does the rixosome maintain repression primarily by clearing newly synthesized RNA or through an additional chromatin-associated function? By mapping direct rixosome targets and testing the consequences of selectively disrupting or restoring rixosome-dependent RNA processing, this work will define how RNA decay safeguards epigenetic silencing during mammalian development.

Eukaryotic cells compartmentalize biological processes in organelles surrounded by membranes with a highly regulated lipid composition. One important regulatory mechanism is the maintenance of a balance between saturated and unsaturated fatty acyl chains in phospholipids. Key players in modulating this unsaturation are fatty acid desaturases. In S. cerevisiae, the sole fatty acid desaturase, Ole1, is essential for cell viability. Its expression is primarily regulated by two transcription factors, Mga2 and Spt23, which are synthesized as ~120 kDa membrane-bound precursors (p120). p120 is cleaved into a ~90 kDa cytosolic fragment (p90) that moves into the nucleus to activate transcription of the OLE1 gene. In the presence of unsaturated fatty acids, precursor cleavage is thought to be suppressed, downregulating Ole1 synthesis. Critical aspects of this pathway remain poorly understood. I aim to address: 1) How is the p120 precursor processed to the active p90 fragment? 2) How does the membrane environment affect p120 levels and processing? 3) How does the p90 fragment function as a transcription factor? Collectively, I hope to provide novel insights into how eukaryotic cells regulate membrane lipid saturation to achieve homeostasis.

The enzyme SETD2 deposits the histone mark H3K36me3, which is found throughout gene bodies and is required for maintaining chromatin architecture, gene regulation, and mRNA splicing. As the main enzyme responsible for H3K36me3 deposition, it is unsurprising that mutations or loss of function in SETD2 are common in various carcinomas and disease. Despite its clinical significance, the mechanistic basis of SETD2 function remains largely unexplored. In my postdoctoral research, I have discovered that SETD2 relies entirely on the RNA polymerase II transcription elongation machinery to deposit H3K36me3. My findings have revealed that RNA polymerase II manipulates the nucleosome to facilitate SETD2 recruitment and recruits additional factors that directly alleviate SETD2 auto-inhibition. My ongoing research in the Farnung lab continues to investigate the detailed activation mechanisms of SETD2, providing explanations for how H3K36me3 is incorporated into gene bodies and how this histone mark regulates downstream processes.

Lysosomes play a crucial role in degrading and recycling cellular materials in eukaryotic cells, functioning as central hubs for lipid metabolism and nutrient sensing. Dysfunctions in lysosomal processes are linked to over 50 rare genetic lysosomal storage diseases (LSDs) affecting diverse biological systems and increasing the risk of neurodegenerative diseases like Parkinson's Disease (PD). 

In my research in the Harper Lab, I am aiming to characterize the molecular signatures of LSDs and the cellular responses of lysosomal dysfunction using unbiased multiomic approaches. For example, we recently demonstrated that dysregulation of cholesterol transport disrupts cellular iron homeostasis with cascading effects on mitochondrial respiratory chain complexes, underscoring the complex interplay between lysosomal function and broader cellular health.

I am now focusing on lysosomal mutants that increase the risk of PD, and utilizing stem-cell derived neuronal models, along with proteomics and microscopy techniques, I intend to investigate the consequences of LSD-PD mutations as well as to explore the molecular and spatial dynamics of cellular compensatory response processes. Through a deeper understanding of the molecular underpinnings of LSD-PD, I hope to pave the way for more targeted and effective treatments for neurodegenerative diseases associated with lysosomal dysfunction.

Wnt morphogens play critical roles in development, regeneration, and cancer by activating the Wnt signaling pathway. However, it is still unknown how Wnt signals are transmitted and received, given their strong lipid-dependent membrane attachment. My research in the Salic Lab aims to understand the release and spread of Wnt ligands from producing cells to activate Wnt signaling in the responding cells. By using cell-based and biochemistry assays, we recently discovered that two classes of secreted proteins, belonging to the Secreted Frizzled-Related Protein (SFRP) and Wnt Inhibitory Factor 1 (WIF1) families, can specifically release Wnts from cells, forming complexes that are highly active in triggering the Wnt pathway. Currently, we are investigating the mechanisms behind this network of extracellular lipid-dependent carriers. Understanding this system is crucial for identifying novel targets to correct pathological signaling and developing strategies to obtain highly active Wnt preparations for regenerative medicine.

Disease mutations in the quality control pathways of a neuronal cell are often the hallmarks of neurodegenerative disease. When the functional compartments of the cell (organelles) become damaged they are marked by the quality control pathway (autophagy) and then the tagged organelles are degraded at the recycling center of the cell (lysosome), but what happens when lysosomes themselves become damaged? During my postdoctoral work in the Harper lab, we directly addressed the mechanisms by which damaged lysosomes are recognized and ultimately degraded by healthy lysosomes through autophagy. It’s also important to keep in mind that organelles can sometimes perform exciting new functions. For instance, in my PhD work, I discovered a protein tethering complex that regulates contact between the endoplasmic reticulum (ER, the site of protein synthesis, lipid synthesis and calcium storage) and endosome budding domains (the main site of signaling receptor cargo sorting in the cell) and this complex regulates the timing of budding domain fission and signaling receptor cargo sorting. My future goal is to continue studying cell biology pathways in human cells and neurons where I will merge my skillsets in assessing the autophagy pathway and monitoring ER dynamics to specifically interrogate the cell process of “ER-phagy” where tiny pieces of the ER are turned over through autophagy.

Olfaction plays an important role in food seeking, reproductive behavior, territorial aggression, and predator escape. In a complex environment, animals will pay attention only to particular sensory cues, and behavioral attraction can depend on internal physiology. For example, hunger is a powerful motivational state; hungry mice will use olfaction to find and locate food sources needed for survival. Recently, we identified a neuronal mechanism by which hunger selectively promotes attraction to food odors over other olfactory cues in mice (Horio and Liberles, Nature, 2021). My research in Liberles lab focuses on the neural circuitry that enhances food odor preference in fasted mice, and more generally how internal state regulates behavior.

Ubiquitylation regulates almost every cellular function and therefore deciphering enzyme-substrate relationships in the ubiquitin-proteasome system (UPS) is essential in understanding how cells work. Deubiquitylating enzymes (DUBs) remove ubiquitin from proteins, thereby controlling their stability or activity. Because the UPS is dysregulated in human diseases, DUBs are being explored as potential drug targets. The human genome encodes around 100 DUBs. While some DUBs are well-characterized, others have few known substrates. My research in the King lab aims to understand the mechanisms that govern the specificity of these enzymes. By using a proteomic approach, developed in collaboration with the Gygi lab, we have identified a wide range of DUB substrates that we are using to understand the principles governing DUB specificity.  

My main project in the Finley lab (HMS – Cell Biology Department) seeks to explain how cells transform into highly differentiated states by remodeling their protein and organelle content. This process is exemplified by erythropoiesis, where human hematopoietic stem cells (HSC) differentiate into mature red blood cells (RBC). During this process, the proteome is completely remodeled, from thousands of different proteins expressed in HSC to a simpler proteome in RBC, where a remarkable 98% of the soluble protein content is hemoglobin. Working together with the Gygi (HMS) and Fleming (BCH) labs, we are aiming to move towards a comprehensive understanding of this degradative program by studying how critical components of the ubiquitin-proteasome system triggers this process. One example is UBE2O, an E2/E3 hybrid enzyme that is upregulated during terminal erythroid differentiation. Employing multiple proteomic techniques, we were able to identify UBE2O as a critical component of the machinery in charge of configuring the proteome during erythropoiesis by targeting, among many others, ribosomal proteins for proteasomal degradation (Nguyen*, Prado* at al., Science, 2017). Altogether, we are working to demonstrate that global proteome remodeling is a fundamental new function of the ubiquitin pathway.

Even though cancer incidence increases dramatically with age, very little is known about how aging pathophysiology affects tumorigenesis beyond the increase in mutational burden over time.  The immune system is especially vulnerable to functional decline with aging, including CD8+ T cells that can selectively kill tumor cells by recognizing features that differ from normal tissue. Surprisingly little is known about how the aged immune system interacts with developing tumors. My research in the Haigis Lab focuses on the discovery of molecular mechanisms dysregulated within aging tumors that regulate local immune responses and tumor progression.