Active learning of enhancers and silencers in the developing neural retina.

Deep learning is a promising strategy for modeling cis-regulatory elements. However, models trained on genomic sequences often fail to explain why the same transcription factor can activate or repress transcription in different contexts. To address this limitation, we developed an active learning approach to train models that distinguish between enhancers and silencers composed of binding sites for the photoreceptor transcription factor cone-rod homeobox (CRX).

represses short-wavelength cone genes to preserve long-wavelength cone and rod photoreceptor identity.

The role of transcription factors in photoreceptor gene regulation is fairly well understood, but knowledge of the cell-type-specific function of transcriptional cofactors remains incomplete. Here, we show that the transcriptional corepressor promotes rod differentiation and represses short-wavelength cone genes in long-wavelength cones in zebrafish. In retinas, red cones are transformed into hybrid red/ultraviolet (UV) cones, green cones are absent, the number of blue cones is approximately doubled, and the number of rods is greatly reduced.

A molecular mechanism for bright color variation in parrots.

Parrots produce stunning plumage colors through unique pigments called psittacofulvins. However, the mechanism underlying their ability to generate a spectrum of vibrant yellows, reds, and greens remains enigmatic. We uncover a unifying chemical basis for a wide range of parrot plumage colors, which result from the selective deposition of red aldehyde- and yellow carboxyl-containing psittacofulvin molecules in developing feathers.

Germline knockout of protects photoreceptors in three distinct mouse models of retinal degeneration.

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting , a transcription factor required for the normal differentiation of rod photoreceptors.

Enzymatic vitamin A production enables red-shifted optogenetics.

Optogenetics is a technology using light-sensitive proteins to control signaling pathways and physiological processes in cells and organs and has been applied in neuroscience, cardiovascular sciences, and many other research fields. Most commonly used optogenetic actuators are sensitive to blue and green light, but red-light activation would allow better tissue penetration and less phototoxicity. Cyp27c1 is a recently deorphanized cytochrome P450 enzyme that converts vitamin A to vitamin A, thereby red-shifting the spectral sensitivity of visual pigments and enabling near-infrared vision in some aquatic species.

Active learning of enhancer and silencer regulatory grammar in photoreceptors.

-regulatory elements (CREs) direct gene expression in health and disease, and models that can accurately predict their activities from DNA sequences are crucial for biomedicine. Deep learning represents one emerging strategy to model the regulatory grammar that relates CRE sequence to function. However, these models require training data on a scale that exceeds the number of CREs in the genome.

A mechanism for red coloration in vertebrates.

Red coloration is a salient feature of the natural world. Many vertebrates produce red color by converting dietary yellow carotenoids into red ketocarotenoids via an unknown mechanism. Here, we show that two enzymes, cytochrome P450 2J19 (CYP2J19) and 3-hydroxybutyrate dehydrogenase 1-like (BDH1L), are sufficient to catalyze this conversion.

Partitioning of gene expression among zebrafish photoreceptor subtypes.

Vertebrate photoreceptors are categorized into two broad classes, rods and cones, responsible for dim- and bright-light vision, respectively. While many molecular features that distinguish rods and cones are known, gene expression differences among cone subtypes remain poorly understood. Teleost fishes are renowned for the diversity of their photoreceptor systems.

Development and genetics of red coloration in the zebrafish relative .

Animal pigment patterns play important roles in behavior and, in many species, red coloration serves as an honest signal of individual quality in mate choice. Among fishes, some species develop erythrophores, pigment cells that contain red ketocarotenoids, whereas other species, like zebrafish () only have yellow xanthophores. Here, we use pearl danio () to assess the developmental origin of erythrophores and their mechanisms of differentiation.

Vitamin A/A chromophore exchange: Its role in spectral tuning and visual plasticity.

Vertebrate rod and cone photoreceptors detect light via a specialized organelle called the outer segment. This structure is packed with light-sensitive molecules known as visual pigments that consist of a G-protein-coupled, seven-transmembrane protein known as opsin, and a chromophore prosthetic group, either 11-cis retinal ('A') or 11-cis 3,4-didehydroretinal ('A'). The enzyme cyp27c1 converts A into A in the retinal pigment epithelium.

Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision.

Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, () is required for expression of long-wavelength-sensitive opsin () in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, , that converts vitamin A into vitamin A to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (, , ).

A genetic mechanism for sexual dichromatism in birds.

Sexual dichromatism, a difference in coloration between males and females, may be due to sexual selection for ornamentation and mate choice. Here, we show that carotenoid-based dichromatism in canaries, a hybrid phenotype that arises in offspring of the sexually dichromatic red siskin and monochromatic canaries, is controlled by the gene that encodes the carotenoid-cleaving enzyme β-carotene oxygenase 2 (). Dichromatism in canaries is explained by differential carotenoid degradation in the integument, rather than sex-specific variation in physiological functions such as pigment uptake or transport.

Enhancer transcription identifies -regulatory elements for photoreceptor cell types.

Identification of cell type-specific regulatory elements (CREs) is crucial for understanding development and disease, although identification of functional regulatory elements remains challenging. We hypothesized that context-specific CREs could be identified by context-specific non-coding RNA (ncRNA) profiling, based on the observation that active CREs produce ncRNAs. We applied ncRNA profiling to identify rod and cone photoreceptor CREs from wild-type and mutant mouse retinas, defined by presence or absence, respectively, of the rod-specific transcription factor (TF) -dependent ncRNA expression strongly correlated with epigenetic profiles of rod and cone photoreceptors, identified thousands of candidate rod- and cone-specific CREs, and identified motifs for rod- and cone-specific TFs.

-regulatory basis of sister cell type divergence in the vertebrate retina.

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key -regulatory features that distinguish them. By comparing open chromatin maps and transcriptomic profiles, we found that while photoreceptor and bipolar cells have divergent transcriptomes, they share remarkably similar -regulatory grammars, marked by enrichment of K50 homeodomain binding sites.

Thyroid hormone regulates distinct paths to maturation in pigment cell lineages.

Thyroid hormone (TH) regulates diverse developmental events and can drive disparate cellular outcomes. In zebrafish, TH has opposite effects on neural crest derived pigment cells of the adult stripe pattern, limiting melanophore population expansion, yet increasing yellow/orange xanthophore numbers. To learn how TH elicits seemingly opposite responses in cells having a common embryological origin, we analyzed individual transcriptomes from thousands of neural crest-derived cells, reconstructed developmental trajectories, identified pigment cell-lineage specific responses to TH, and assessed roles for TH receptors.

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis.

Background: Dysembryoplastic neuroepithelial tumors (DNETs) are uncommon neural tumors presenting most often in children and young adults and associated with intractable seizures. Rare midline neoplasms with similar histological features to those found in DNETs have been described near the septum pellucidum and termed "DNET-like neoplasms of the septum pellucidum." Due to their rarity, these tumors have been described in just a few reports and their genetic alterations sought only in small series.

A non-coding region near controls head colour polymorphism in the Gouldian finch.

Discrete colour morphs coexisting within a single population are common in nature. In a broad range of organisms, sympatric colour morphs often display major differences in other traits, including morphology, physiology or behaviour. Despite the repeated occurrence of this phenomenon, our understanding of the genetics that underlie multi-trait differences and the factors that promote the long-term maintenance of phenotypic variability within a freely interbreeding population are incomplete.

A massively parallel reporter assay reveals context-dependent activity of homeodomain binding sites in vivo.

Cone-rod homeobox (CRX) is a paired-like homeodomain transcription factor (TF) and a master regulator of photoreceptor development in vertebrates. The in vitro DNA binding preferences of CRX have been described in detail, but the degree to which in vitro binding affinity is correlated with in vivo enhancer activity is not known. In addition, paired-class homeodomain TFs can bind DNA cooperatively as both homodimers and heterodimers at inverted TAAT half-sites separated by 2 or 3 nucleotides.

Evolution, Development and Function of Vertebrate Cone Oil Droplets.

To distinguish colors, the nervous system must compare the activity of distinct subtypes of photoreceptors that are maximally sensitive to different portions of the light spectrum. In vertebrates, a variety of adaptations have arisen to refine the spectral sensitivity of cone photoreceptors and improve color vision. In this review article, we focus on one such adaptation, the oil droplet, a unique optical organelle found within the inner segment of cone photoreceptors of a diverse array of vertebrate species, from fish to mammals.

Cambrian origin of the CYP27C1-mediated vitamin A-to-A switch, a key mechanism of vertebrate sensory plasticity.

The spectral composition of ambient light varies across both space and time. Many species of jawed vertebrates adapt to this variation by tuning the sensitivity of their photoreceptors via the expression of CYP27C1, an enzyme that converts vitamin A into vitamin A, thereby shifting the ratio of vitamin A-based rhodopsin to red-shifted vitamin A-based porphyropsin in the eye. Here, we show that the sea lamprey (), a jawless vertebrate that diverged from jawed vertebrates during the Cambrian period (approx.