Despite the paucity of other examples, the importance of NOVA1 and NOVA2 in modulating neuronal gene expression underscores the possibility that lineage-specific splicing factors regulate gene expression in other tissues. Further, genes encoding multiple proteins that possess disparate functions in transcription and splicing may enhance lineage-specific gene expression in regulating specialized cell functions. This model is best represented by tissue-restricted expression of two isoforms of the Wilms’ tumor gene WT1, WT and WT1, which regulate gene transcription and RNA processing, respectively. Development and maintenance of a functional intestinal epithelium is dependent on complex temporal and spatial regulation of gene expression and the resulting proteome. This process is regulated in part by a set of intestine-specific proteins, including the transcription factor CDX2. CDX2, a caudal-related intestine-specific transcription factor, plays a central role in regulating the development and maintenance of the intestinal epithelium canonically through promoter binding and activation of target genes, which largely comprise the mature enterocyte phenotype. These include proteins such as guanylyl cyclase C, LI-cadherin, sucrase JTP-74057 isomaltase, and lactase. Expression of this gene signature influences homeostatic processes in intestinal epithelial cells including proliferation and differentiation. The canonical CDX2 gene comprises three exons and two introns encoding a 313 amino acid protein with an amino-terminal transactivation region and carboxy-terminal homeobox binding domain. CDX2 regulates trophectoderm integrity during embyrogenesis and postnatally the development and maintenance of the intestinal epithelium. We report here the discovery and characterization of a novel CDX2 transcript, CDX2/AS, generated by alternative splicing, that encodes a CDX2 protein possessing the activation domain but a truncated homeobox juxtaposed distally by a novel 45 amino acid domain enriched in serine and arginine residues. Although contemporaneously expressed and localized in the nucleus, CDX2 and CDX2/AS function independently as transcription and splicing factors, respectively, establishing CDX2 as the first gene to encode intestine-specific proteins that regulate transcription and premRNA processing. In intestine, LIcadherin, and sucrose isomaltase. Paradoxically, in other studies, CDX2 increases expression of pro-proliferative genes, increases anchorage-independent growth, undergoes overexpression in colonic tumors.