Genomic analysis of transcriptional networks directing progression of cell states during MGE development

ABSTRACTDespite a common understanding that Gli TFs are utilized to reiterate a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. We demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the bHLH TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis further revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, ‘divergent’ Gli binding motifs (dGBMs). Functional validation revealed these dGBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.

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Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks

eLife ◽

10.7554/elife.56450 ◽

2020 ◽

Vol 9 ◽

Author(s):

Kelsey H Elliott ◽

Xiaoting Chen ◽

Joseph Salomone ◽

Praneet Chaturvedi ◽

Preston A Schultz ◽

...

Keyword(s):

Transcriptional Activity ◽

Genomic Analysis ◽

Regulatory Elements ◽

Transcriptional Networks ◽

Motif Analysis ◽

Binding Motifs ◽

Helix Loop Helix ◽

Synergistic Activation ◽

Common Understanding ◽

Dependent Mechanism

Despite a common understanding that Gli TFs are utilized to convey a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, ‘divergent’ Gli-binding motifs (dGBMs). Functional validation revealed these dGBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.

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Ruminant-specific retrotransposons shape regulatory evolution of bovine immunity

10.1101/2021.10.01.462810 ◽

2021 ◽

Author(s):

Conor J Kelly ◽

Carol Chitko-McKown ◽

Edward B Chuong

Keyword(s):

Genomic Analysis ◽

Transcriptional Networks ◽

Immune Gene ◽

Regulatory Evolution ◽

Population Genomic ◽

Insertion Sites ◽

Gene Regulatory ◽

Multiple Species ◽

Polymorphic Insertion ◽

Inducible Gene

Cattle are an important livestock species, and mapping the genomic architecture of agriculturally relevant traits such as disease susceptibility is a major challenge in the bovine research community. Lineage-specific transposable elements (TEs) are increasingly recognized to contribute to gene regulatory evolution and variation, but this possibility has been largely unexplored in ruminant genomes. We conducted epigenomic profiling of the type II interferon (IFN) response in bovine cells, and found thousands of ruminant-specific TEs including MER41_BT and Bov-A2 elements predicted to act as IFN-inducible enhancer elements. CRISPR knockout experiments in bovine cells established that critical immune factors including IFNAR2 and IL2RB are transcriptionally regulated by TE-derived enhancers. Finally, population genomic analysis of 39 individuals revealed that a subset of TE-derived enhancers represent polymorphic insertion sites in modern cattle. Our study reveals that lineage-specific TEs have shaped the evolution of ruminant IFN responses, and potentially continue to contribute to immune gene regulatory differences across modern breeds and individuals. Together with previous work in human cells, our findings demonstrate that lineage-specific TEs have been independently co-opted to regulate IFN-inducible gene expression in multiple species, supporting TE co-option as a recurrent mechanism driving the evolution of IFN-inducible transcriptional networks.

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Genomic analysis of C-type lectins

Biochemical Society Symposium ◽

10.1042/bss0690059 ◽

2002 ◽

Vol 69 ◽

pp. 59-72 ◽

Cited By ~ 85

Author(s):

Kurt Drickamer ◽

Andrew J. Fadden

Keyword(s):

Biological Effects ◽

Cell Signalling ◽

Genomic Analysis ◽

Binding Activity ◽

Immunoglobulin Superfamily ◽

Carbohydrate Binding ◽

Carbohydrate Recognition ◽

Calcium Dependent ◽

Binding Domains ◽

Carbohydrate Recognition Domains

Many biological effects of complex carbohydrates are mediated by lectins that contain discrete carbohydrate-recognition domains. At least seven structurally distinct families of carbohydrate-recognition domains are found in lectins that are involved in intracellular trafficking, cell adhesion, cell–cell signalling, glycoprotein turnover and innate immunity. Genome-wide analysis of potential carbohydrate-binding domains is now possible. Two classes of intracellular lectins involved in glycoprotein trafficking are present in yeast, model invertebrates and vertebrates, and two other classes are present in vertebrates only. At the cell surface, calcium-dependent (C-type) lectins and galectins are found in model invertebrates and vertebrates, but not in yeast; immunoglobulin superfamily (I-type) lectins are only found in vertebrates. The evolutionary appearance of different classes of sugar-binding protein modules parallels a development towards more complex oligosaccharides that provide increased opportunities for specific recognition phenomena. An overall picture of the lectins present in humans can now be proposed. Based on our knowledge of the structures of several of the C-type carbohydrate-recognition domains, it is possible to suggest ligand-binding activity that may be associated with novel C-type lectin-like domains identified in a systematic screen of the human genome. Further analysis of the sequences of proteins containing these domains can be used as a basis for proposing potential biological functions.

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