Neural crest cells (NCCs), often termed the "fourth germ layer," delaminate from the neural tube and give rise to diverse cell types such as cartilage, bone, connective tissue, melanocytes, and Schwann cells. Their fate specification is tightly regulated by microenvironmental cues and follows a stepwise restriction from a pluripotent to a unipotent state. Understanding how NCCs make fate decisions is crucial, as errors in this process are linked to a range of developmental disorders. The NCC system offers a powerful paradigm for studying the interplay between intrinsic gene regulatory networks and extrinsic signaling cues during lineage specification. To dissect the mechanisms underlying NCC fate decisions, we use melanocytes as a model system, as they represent a well-defined and tractable lineage derived from the neural crest, allowing us to explore both fundamental principles of developmental biology and disease relevance. 

Epigenetic Regulation of NCC Fate: The Role of Histone Variants 

Investigating cell-intrinsic regulators of NCC specification is a growing field, with epigenetic mechanisms emerging as key players. Chromatin modifiers like histone deacetylases and DNA methyltransferases are known modulators, but tissue-specific histone variants are increasingly recognized for their roles in fate biasing. Notably, H2A.Z.2 promotes melanocyte specification by regulating key transcription factors such as MITF and SOX9.

Reference: Histone variant dictates fate biasing of neural crest cells to melanocyte lineage 

Our ongoing work explores the role of another variant, H3.3, in NCC fate determination. We employ multi-omics approaches, including single-cell RNA-seq and ATAC-seq, alongside NCC-specific knockout models to unravel the epigenetic landscape shaping lineage specification.

Unraveling Cell Fate Decisions Through Small RNA Pathways 

Building on this framework, we aim to identify novel genes acting upstream or downstream of key epigenetic regulators that influence neural crest fate specification to melanocytes. One such candidate is RNASEK, which we found to be expressed in neural crest cells and later in progenitors committed to the melanocyte lineage. RNASEK encodes an endoribonuclease previously implicated in piRNA precursor processing in the reproductive cells of Bombyx mori. Based on this, we hypothesize that RNASEK may regulate neural crest fate decisions through its potential role in piRNA biogenesis. By modulating transcriptional, post-transcriptional, or translational pathways, RNASEK could add an additional layer of control to the complex regulatory landscape guiding lineage specification within the neural crest.

Neural crest-derived cells differentiate into a variety of cell types, but disruptions in their developmental trajectories can lead to malignancies such as melanoma, neuroblastoma, and glioblastoma. Melanoma, arising from pigment-producing melanocytes, is uniquely suited for study due to its combination of neural crest origin, extreme metastatic potential, and notable resistance to current therapies. This makes melanoma an ideal entry point to dissect how developmental programs are subverted in cancer. Insights gained here will lay the groundwork for expanding our investigations into other neural crest-associated malignancies with shared lineage vulnerabilities. 

Molecular Switches Connecting Melanocyte Development to Melanoma Susceptibility 

Our recent study reveals that MGAT4B, a glycosyltransferase enriched in pigment progenitors, regulates melanocyte migration and stem cell pool formation by modulating selective N-glycan branching on key proteins like KIT, TYRP1, and GPNMB. Loss of mgat4b disrupts adhesion, impairs progenitor persistence, and prevents melanoma initiation in BRAFV600E zebrafish models. Elevated MGAT4B expression correlates with poor survival in melanoma patients, highlighting its dual role in development and disease.

Reference: Selective N-glycosylation regulates melanocyte development and melanoma progression 

Pigmentation-Induced Genotoxic Stress

Another study revealed that sustained pigmentation itself, often considered a protective trait, can paradoxically induce oxidative DNA damage. This triggers the recruitment of the translesion DNA polymerase Polκ—a specialized repair enzyme that enables melanocyte survival under genotoxic stress, redefining our view of pigment as a biologically active and stress-linked trait. Our study proposes that UV-induced melanogenesis, through lesion bypass by Polκ, may potentially contribute to key melanoma driver mutations such as BRAF V600E. While Polκ helps maintain melanocyte homeostasis, its dual role in error-prone translesion synthesis and checkpoint control highlights an underappreciated mutagenic risk linked to melanin. 

Reference: Sustained pigmentation causes DNA damage and invokes translesion polymerase Polκ for repair 

Together, our findings establish melanocytes as a dynamic model for uncovering how developmental cues and stress-adaptive responses intersect to shape melanoma susceptibility. By linking specific developmental regulators like MGAT4B and damage response factors such as Polκ to melanoma initiation, we reveal critical nodes where homeostatic mechanisms may be rewired during tumorigenesis. Building on this foundation, future research will extend into uncovering more of such modulators in melanoma and other neural crest-derived cancers to determine how lineage-specific programs, DNA damage, and repair pathways converge to influence disease onset, progression, and therapeutic resistance. 

Another research theme of our lab investigates how UV radiation induces distinct pigmentation and proliferation programs in melanocytes. Through single-cell RNA and ATAC sequencing in human and zebrafish skin, we identified two transcriptionally distinct melanocyte subpopulations, indicating a cell-intrinsic bistable system. These states arise stochastically and are stably inherited, as demonstrated by fluctuation tests and lineage tracing. By integrating multi-omics data with enhancer mapping (H3K27ac), we reconstructed a gene regulatory network (GRN) that underpins this cell state divergence. External signals reinforce either pigmentation or proliferation, with epigenetic imprinting via histone acetylation maintaining the mature pigmenting state.

Reference: Stochastic expression of proliferation or maturation programs enable a rapid and sustainable pigmentation response 

Ongoing work in our lab focuses on uncovering similar hidden heterogeneity within seemingly homogenous cell populations, using melanocytes as a model. This has broader implications for understanding cell fate decisions in development and disease. Notably, such cell state heterogeneity parallels that seen in tumors, where rare subpopulations like cancer stem cells may drive therapy resistance and relapse. Our findings offer a foundation to explore how stochastic and epigenetic mechanisms contribute to functional diversity and resilience in cellular systems.

Because curiosity doesn’t follow comfort zones.

At TNV Lab, we believe that the most impactful discoveries often emerge from asking questions no one else is asking — or daring to ask them differently. This section highlights research born out of raw curiosity, often beyond the traditional boundaries of our core interests, and led to insights that bridged gaps across developmental biology, evolution, and virology.

Vitiligo: A Paradox of Protection

By investigating why vitiligo lesions show lower mutation burden, we discovered enhanced DNA repair and rapid cell turnover in depigmented skin—features that may explain reduced cancer risk. This curiosity-driven finding challenges assumptions and reveals vitiligo as a state of active cellular protection. 

Reference:  vitiligo lesions may represent a reprogrammed, actively regenerating tissue niche  

Another study identifies Myg1 as a conserved dual-localized 3′-5′ RNA exonuclease that coordinates RNA processing in both the nucleolus and mitochondrial matrix. By regulating translation in these compartments, Myg1 fine-tunes nucleo-mitochondrial communication critical for cellular homeostasis. Disruption of this coordination implicates Myg1 as a potential molecular contributor to vitiligo, a chronic depigmenting disorder linked to mitochondrial dysfunction. We further aim to decode Myg1 role in melanocyte survival at a deeper molecular level

Reference: Myg1 exonuclease couples the nuclear and mitochondrial translational programs through RNA processing 

Climate, Keratin, and the Skin’s Evolutionary Code

Another study of ours revealed that genes involved in keratinization and epidermal differentiation have undergone accelerated evolution in humans, shaped by environmental pressures like climate. This often-overlooked skin function plays a vital role in adaptation, working in tandem with pigmentation to modulate trans-epidermal water loss across populations. 

Reference: Climate, Keratin, and the Skin’s Evolutionary Code 

Decoding Viral Proofreading: The Achilles’ Heel of Coronaviruses

Coronaviruses possess a unique proofreading exonuclease that detects and removes mismatched nucleotides, making them unusually resistant to nucleoside analog-based antivirals. Our ongoing project delves into the molecular mechanism of this proofreading activity to uncover how mismatches are recognized and corrected. By combining structural biology, evolutionary insight, and computational modeling, we aim to identify vulnerabilities within this proofreading machinery. 

This reflects our lab’s core philosophy—pushing boundaries to explore unconventional paths with potential for high therapeutic impact. At TNV Lab, we actively encourage projects that stray from the expected path. Whether it's a side project sparked by a journal club discussion or a long-shot idea born from scientific intuition, our lab provides the intellectual freedom and support to chase the unknown. Because the edge of science is never a straight line — and sometimes, what seems off-track is exactly where the breakthrough lies.