Career in Biology

I am a postdoc at the MRC centre for regenerative medicine of the University of Edinburgh, in the laboratory of Donal O’Carroll

I started my am postdoc at EMBL in an interdisciplinary project between the laboratories of Donal at EMBL monterotondo and Anton Enright at EMBL-EBI.

Research achievements during my PhD.

CPEB2 subfamily 3'UTRs

Background. Developmental biology in higher organisms critically depends on RNA mediated gene expression regulation. As a consequence, the length and complexity of 3' untranslated regions (3'UTRs) of mRNAs is dramatically expanded in mammals. The aim of my Ph.D. was to make sense of the different signatures present in the 3’UTRs, in particular miRNA targets and highly conserved elements.

Research. I showed that CPEB2, CPEB3 and CPEB4 transcripts are regulated by a shared ancestral miRNA signature¹. Moreover, I showed that the miRNA binding sites preceded the generation of highly conserved elements in their 3'UTRs (Figure 1).

Figure 1. The 3’UTRs of CPEB2, CPEB3 and CPEB4 share an ancestral miRNA signature that preceded the generation of highly conserved elements. a, Evolution of the CPEB2 subfamily consisting of two duplications preceding vertebrate speciation. The 3’UTR of the ancestral and current CPEBs for different vertebrates is depicted. The binding sites for different miRNA are indicated. b, Alignment of segments of human CPEB2, CPEB3 and CPEB4 3’UTRs. c, Alignment of the same segment of CPEB2 3’UTRs now between different vertebrates. The binding sites for mir-26 and mir-92 are shown.

3'UTR annotation

The explosion of genomic and transcriptomic data created a bottleneck in the gene annotation pipelines at the level of data analysis. While working on the CPEBs, I noticed that the long 3'UTR isoforms of these and other genes were mis-annotated. Importantly, these isoforms were highly conserved across vertebrates and abundantly expressed in the brain (Figure 2). I then moved on to develop different approaches to annotate 3'UTRs in vertebrates. I found a few hundred mis-annotated genes in mice and humans and a few thousand in other vertebrates². I also showed that long 3'UTRs tend to be misclassified as long non-coding RNAs.

Figure 2. Identification of 3’ ends for transcripts encoding different K⁺ channels. a, Genomic region encoding the 3’UTRs of Kcnq3 (left panel) and Kcnb1 (right panel). The annotated transcripts are shown on top (Ensembl) together with mapping ESTs, the conservation score for the genomic region (PhyloP) and RNASeq reads from brain (B), testis (T) and heart (H). The proposed 3’ ends are indicated with colored arrowheads. b, Northern blots of brain (B), testis (T) and heart (H) using probes for Kcnq3 (left) and Kcnb1 (right) are shown. The bands corresponding to the proposed new 3’ ends are indicated by the arrowheads.

Perspective. In the study of the CPEB transcripts, I showed that miRNA binding sites embedded in highly conserved stretches of 3’UTRs are functional and more interestingly, they also preceded the formation of these highly conserved elements. Also, the annotations that we proposed for conserved 3’UTRs were later validated by others³ and with time incorporated to the commonly used databases.

1.        Morgan, M., Iaconcig, A. & Muro, A. F. CPEB2, CPEB3 and CPEB4 are coordinately regulated by miRNAs recognizing conserved binding sites in paralog positions of their 3’-UTRs. Nucleic Acids Res. 38, 7698–7710 (2010).

2.        Morgan, M., Iaconcig, A. & Muro, A. F. Identification of 3’ gene ends using transcriptional and genomic conservation across vertebrates. BMC Genomics 13, 708 (2012).

3.        Miura, P. et al. Widespread and extensive lengthening of 3 ′ UTRs in the mammalian brain Widespread and extensive lengthening of 3 9 UTRs in the mammalian brain. 812–825 (2013). doi:10.1101/gr.146886.112

Research achievements during my undergraduate studies

Research achievements during my undergraduate studies.

Background. The early 2000s were characterized by an explosion in the number of genomes sequenced for different species. With the preliminary annotation of the vertebrates’ genomes, the clustered protocadherins emerged as the strongest candidates to provide single cell identity to neurons. I decided to look at their evolution to gain insights about their function. 

Research. I showed how the protocadherin gene clusters evolved in human and mouse after the divergence of the species (Morgan, 2008). In particular, I found that a unique unit of evolution explains all the recent duplication events for all the protocadherin clusters (Figure 1).
Perspective. The unit of evolution turned out to encode for the C-terminal region of a protocadherin together with the promoter region and the N-terminal region of the protocadherin immediately downstream in the cluster. Whether this form of evolution has functional implication is not known. 

Figure 1. Evolution of part of the human b-protocadherin cluster. Each block represents a gene. The light colored part of the gene encodes for the C-terminal portion of the protein.

Morgan, M. Models for the recent evolution of protocadherin gene clusters. Biocell 32, 9–26 (2008).