Bat Accelerated Regions Identify a Bat Forelimb Specific Enhancer in the HoxD Locus

TY - JOUR

T1 - Bat Accelerated Regions Identify a Bat Forelimb Specific Enhancer in the HoxD Locus

AU - Booker, Betty M

AU - Friedrich, Tara

AU - Mason, Mandy K

AU - VanderMeer, Julia E

AU - Zhao, Jingjing

AU - Eckalbar, Walter L

AU - Logan, Malcolm

AU - Illing, Nicola

AU - Pollard, Katherine S

AU - Ahituv, Nadav

PY - 2016/3

Y1 - 2016/3

N2 - The molecular events leading to the development of the bat wing remain largely unknown, and are thought to be caused, in part, by changes in gene expression during limb development. These expression changes could be instigated by variations in gene regulatory enhancers. Here, we used a comparative genomics approach to identify regions that evolved rapidly in the bat ancestor, but are highly conserved in other vertebrates. We discovered 166 bat accelerated regions (BARs) that overlap H3K27ac and p300 ChIP-seq peaks in developing mouse limbs. Using a mouse enhancer assay, we show that five Myotis lucifugus BARs drive gene expression in the developing mouse limb, with the majority showing differential enhancer activity compared to the mouse orthologous BAR sequences. These include BAR116, which is located telomeric to the HoxD cluster and had robust forelimb expression for the M. lucifugus sequence and no activity for the mouse sequence at embryonic day 12.5. Developing limb expression analysis of Hoxd10-Hoxd13 in Miniopterus natalensis bats showed a high-forelimb weak-hindlimb expression for Hoxd10-Hoxd11, similar to the expression trend observed for M. lucifugus BAR116 in mice, suggesting that it could be involved in the regulation of the bat HoxD complex. Combined, our results highlight novel regulatory regions that could be instrumental for the morphological differences leading to the development of the bat wing.

AB - The molecular events leading to the development of the bat wing remain largely unknown, and are thought to be caused, in part, by changes in gene expression during limb development. These expression changes could be instigated by variations in gene regulatory enhancers. Here, we used a comparative genomics approach to identify regions that evolved rapidly in the bat ancestor, but are highly conserved in other vertebrates. We discovered 166 bat accelerated regions (BARs) that overlap H3K27ac and p300 ChIP-seq peaks in developing mouse limbs. Using a mouse enhancer assay, we show that five Myotis lucifugus BARs drive gene expression in the developing mouse limb, with the majority showing differential enhancer activity compared to the mouse orthologous BAR sequences. These include BAR116, which is located telomeric to the HoxD cluster and had robust forelimb expression for the M. lucifugus sequence and no activity for the mouse sequence at embryonic day 12.5. Developing limb expression analysis of Hoxd10-Hoxd13 in Miniopterus natalensis bats showed a high-forelimb weak-hindlimb expression for Hoxd10-Hoxd11, similar to the expression trend observed for M. lucifugus BAR116 in mice, suggesting that it could be involved in the regulation of the bat HoxD complex. Combined, our results highlight novel regulatory regions that could be instrumental for the morphological differences leading to the development of the bat wing.

KW - Animals

KW - Chiroptera/genetics

KW - Embryo, Mammalian

KW - Forelimb/growth & development

KW - Gene Expression Regulation, Developmental

KW - Genomics

KW - Homeodomain Proteins/biosynthesis

KW - Mice

KW - Organogenesis/genetics

KW - Sequence Alignment

KW - Sequence Analysis

KW - Transcription Factors/biosynthesis

KW - Vertebrates/genetics

KW - Wings, Animal/growth & development

U2 - 10.1371/journal.pgen.1005738

DO - 10.1371/journal.pgen.1005738

M3 - Article

C2 - 27019019

SN - 1553-7390

VL - 12

SP - e1005738

JO - PL o S Genetics

JF - PL o S Genetics

IS - 3

ER -